Substance use patterns in 9-10 year olds: Baseline findings from the adolescent brain cognitive development (ABCD) study.

BACKGROUND: The Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12. METHODS: This study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort's early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD). PRIMARY RESULTS: At baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine, <0.1 % used any other drug of abuse). Analyses revealed that total caffeine use and early alcohol sipping were associated with demographic variables (p's<.05), externalizing symptoms (caffeine p = 0002; sipping p = .0003), and parental history of AUD (sipping p = .03). CONCLUSIONS: ABCD Study participants aged 9-10 years old reported caffeine use and alcohol sipping experimentation, but very rare other SU. Variables linked with early childhood alcohol sipping and caffeine use should be examined as contributing factors in future longitudinal analyses examining escalating trajectories of SU in the ABCD Study cohort.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Nanoscale structural and electrical properties of graphene grown on AlGaN by catalyst-free chemical vapor deposition.

The integration of graphene (Gr) with nitride semiconductors is highly interesting for applications in high-power/high-frequency electronics and optoelectronics. In this work, we demonstrated the direct growth of Gr on Al0.5Ga0.5N/sapphire templates by propane (C3H8) chemical vapor deposition at a temperature of 1350 °C. After optimization of the C3H8 flow rate, a uniform and conformal Gr coverage was achieved, which proved beneficial to prevent degradation of AlGaN morphology. X-ray photoemission spectroscopy revealed Ga loss and partial oxidation of Al in the near-surface AlGaN region. Such chemical modification of a ∼2 nm thick AlGaN surface region was confirmed by cross-sectional scanning transmission electron microscopy combined with electron energy loss spectroscopy, which also showed the presence of a bilayer of Gr with partial sp2/sp3 hybridization. Raman spectra indicated that the deposited Gr is nanocrystalline (with domain size ∼7 nm) and compressively strained. A Gr sheet resistance of ∼15.8 kΩ sq-1 was evaluated by four-point-probe measurements, consistently with the nanocrystalline nature of these films. Furthermore, nanoscale resolution current mapping by conductive atomic force microscopy indicated local variations of the Gr carrier density at a mesoscopic scale, which can be ascribed to changes in the charge transfer from the substrate due to local oxidation of AlGaN or to the presence of Gr wrinkles.

[Attitude of psychiatrists and psychiatry residents in Lebanon towards restraint and informed consent]. / Attitude des psychiatres et internes en psychiatrie au Liban vis-à-vis de la contention et du consentement éclairé.

OBJECTIVES: Psychiatry differs from the rest of medical specialties by the unique character of its pathologies, which makes ethical reflection difficult, including the collection of informed consent and the use of restraint and the seclusion-room. This reflection can be affected by subjectivity and a variety of influences, hence the interest of studying the attitude of psychiatrists and residents in psychiatry in Lebanon with regard to restraint and informed consent. METHODS: We collected data using an anonymous questionnaire that we sent as a Google form to Lebanese psychiatrists and psychiatry residents by email and phone messages. The descriptive analysis was done using Microsoft Excel software, and the analytical analysis was done using the SPSS software and the following statistical tests: independent-sample test and the Mann Whitney U test. RESULTS: Forty people responded, including 19 men and 21 women (16 psychiatric interns, 15 university psychiatrists and 9 non-university psychiatrists). Concerning the questions related to the use of restraint, 70% did not find that it is being commonly used in hospital practice. However, 92.5% would use it to counter the patient's dangerousness and 60% to help deliver treatment. 57.5% did not find the repeated usage of restraint as a dehumanization of care, but the majority (70%) agreed with the need for temporal limitation of any form of restraint. As for the ability to consent, 90% considered a patient in a psychotic state as unfit to consent. CONCLUSIONS: Restraint is considered uncommon by psychiatrists and psychiatric residents in Lebanon and must remain an option of last resort with efforts being made upstream in order to avoid situations where the use of restraint becomes mandatory. Post critical thinking is paramount, and restraint should never respond to a lack of manpower or a security goal. Informed consent is one of the most important guarantors of the principle of autonomy, and must be sought in each patient, individually. Finally, no significant difference was found between the subgroups, which would therefore become a single population. Ethical reflection would therefore be directly linked to the population. Mental illnesses are becoming more common and an important source of morbidity worldwide. It is our role to ensure the dignity of the mentally ill. The introduction of the Psychiatric Nurse Diploma, an increase in the relational approach to the training of psychiatrists in Lebanon, and an increase in the number of health care teams may help to maximize the ability of capacity.

Al5+αSi5+δN12, a new Nitride compound.

The family of III-Nitride semiconductors has been under intensive research for almost 30 years and has revolutionized lighting applications at the dawn of the 21st century. However, besides the developments and applications achieved, nitride alloys continue to fuel the quest for novel materials and applications. We report on the synthesis of a new nitride-based compound by using annealing of AlN heteroepitaxial layers under a Si-atmosphere at temperatures between 1350 °C and 1550 °C. The structure and stoichiometry of this compound are investigated by high resolution transmission electron microscopy (TEM) techniques and energy dispersive X-Ray (EDX) spectroscopy. Results are supported by density functional theory (DFT) calculations. The identified structure is a derivative of the parent wurtzite AlN crystal where the anion sublattice is fully occupied by N atoms and the cation sublattice is the stacking of 2 different planes along <0001>: The first one exhibits a ×3 periodicity along <11-20> with 1/3 of the sites being vacant. The rest of the sites in the cation sublattice are occupied by an equal number of Si and Al atoms. Assuming a semiconducting alloy, a range of stoichiometries is proposed, Al5+αSi5+δN12 with α being between -2/3 and 1/4 and δ between 0 and 3/4.

Remote epitaxy using graphene enables growth of stress-free GaN.

The properties of group III-Nitrides (III-N) such as a large direct bandgap, high melting point, and high breakdown voltage make them very attractive for optoelectronic applications. However, conventional epitaxy on SiC and sapphire substrates results in strained and defective films with consequently poor device performance. In this work, by studying the nucleation of GaN on graphene/SiC by MOVPE, we unambiguously demonstrate the possibility of remote van der Waals epitaxy. By choosing the appropriate growth conditions, GaN crystals can grow either in-plane misoriented or fully epitaxial to the substrate. The adhesion forces across the GaN and graphene interface are very weak and the micron-scale nuclei can be easily moved around. The combined use of x-ray diffraction and transmission electron microscopy demonstrate the growth of stress-free and dislocation-free crystals. The high quality of the crystals was further confirmed by photoluminescence measurements. First principles calculations additionally highlighted the importance of the polarity of the underlying substrate. This work lays the first brick towards the synthesis of high quality III-N thin films grown via van der Waals epitaxy.

The advisory process for anticancer drug regulation: a global perspective.

PURPOSE: This paper summarizes the role of external advisors in oncology drug development and regulation from a global perspective. DESIGN: Recently, representatives from the United States Food and Drug Administration, European Medicines Agency, the Japanese Pharmaceuticals and Medical Devices Agency, the Australian Therapeutic Goods Administration and Health Canada held a meeting in conjunction with the American Society of Clinical Oncology meeting. The role of external advisors in oncology drug development and regulation in each of these jurisdictions was presented and discussed. RESULTS: All regulatory bodies described have experience with two forms of outside expertise: advice from individual experts and advice from a group of experts assembled as an advisory group. Regulatory jurisdictions use individual experts variably. In some regions, individual experts provide advice based on knowledge and experience during the drug development phase or in the planning phase for the submission of a drug registration package. In other regions, these individuals serve as external evaluators with the primary responsibility for the review of a clinical trials package submitted for drug registration. Advisory boards have been formalized in all jurisdictions discussed. Advisory boards have a role in discussing specific applications as well as broad policy issues. A common theme is a composition of a core panel of experts with augmentation by additional expertise as needed for consideration of specific scientific questions. In all jurisdictions, advisory board recommendations are not binding on the regulatory body. CONCLUSIONS: Global oncology drug development and registration involves the use of experts by regulatory authorities. The types of experts needed, the expert's role and the transparency of the advisory process reflect the individual needs in different regions.

Review article: tolevamer, a novel toxin-binding polymer: overview of preclinical pharmacology and physicochemical properties.

BACKGROUND: Tolevamer is a novel toxin-binding polymer that is currently being investigated in clinical trials for the treatment of patients who have Clostridium difficile-associated diarrhoea. AIMS: To summarize the results of in vitro and in vivo preclinical studies of tolevamer. In contrast to antibiotics, tolevamer binds C. difficile toxins to interrupt toxin-mediated intestinal inflammation and tissue damage, and does not demonstrate direct antimicrobial activity. METHODS: Pharmacokinetics/pharmacodynamics were studied in rats and dogs; efficacy was studied in a hamster model. RESULTS: Studies in rats and dogs indicate that tolevamer is essentially non-absorbed from the gastrointestinal tract and show that drug interactions with commonly used therapies are unlikely. Pharmacologic studies indicate that tolevamer reduces disease severity and recurrence rates in the hamster model of C. difficile-associated diarrhoea and blocks the enterotoxic effects of toxin A in rat ileum. The binding parameters calculated for the interaction of tolevamer with toxins A and B provide a reasonable physicochemical model that supports the potential clinical utility of tolevamer. CONCLUSIONS: These preclinical results are consistent with the effectiveness and safety profile of tolevamer observed in clinical studies in patients with C. difficile-associated diarrhoea.

Anticancer drug discovery and development throughout the world.

This year's American Society of Clinical Oncology International Symposium devoted 2 hours to a lively discussion of various aspects of anticancer drug discovery and development throughout the world. The scientific program started with an overview of efforts directed toward promoting international collaboration in natural product-derived anticancer drug discovery. This was followed by a discussion on the importance of interethnic differences and pharmacogenetics in anticancer drug development. Thereafter, this part of the program was completed by a description of the activities of the newly created Singapore-Hong Kong-Australia Drug Development Consortium and an overview of the contribution of Japan to anticancer drug development. The logistics and regulatory aspects of clinical trials with new anticancer agents in different parts of the world were then presented, with an emphasis on Europe, North America, and Japan. The program was completed with a panel discussion of the efforts to harmonize the exchange of clinical data originating from one region of the globe with other territories, with input from official representatives of the United States Food and Drug Administration and the Medical Devices Evaluation Center of Japan.

Oral hygiene and lifestyle correlates among new undergraduate university students in Lebanon.

Little is known about Lebanese college students' oral hygiene and the factors associated with how often they brush their teeth. The authors used a structured questionnaire to investigate these issues in a sample of 954 new students at the American University of Beirut in fall 1998. The results indicated poor flossing habits and unfavorable dietary habits among the group. Moreover, using logistic regression analysis, they found that variables such as gender, father's education, exercise, and dietary habits, were significantly correlated with the how frequently the students brushed their teeth. Appropriate promotional activities to improve flossing and dietary habits associated with better oral hygiene are recommended. In addition, the authors call for further research to elaborate on the deficiencies in oral health practices and explore a wider variety of lifestyle behaviors and their correlation.

A rare case of renal hemangioma presenting as polycythemia.

Instances of renal cell carcinoma and erythropoietin-producing renal cysts presenting as polycythemia are well documented. To our knowledge, no case of hemangioma presenting as polycythemia has been reported. We present a case of a 39-year-old man with a 5-year history of polycythemia requiring phlebotomy every 3 months. Computed tomography revealed a 6 to 7-cm right upper pole renal mass. The patient underwent right radical nephrectomy, and pathologic examination revealed the mass to be a capillary hemangioma. The patient has not required phlebotomy for 1 year since the removal of the hemangioma.

Molecular confirmation of Ewing sarcoma.

OBJECTIVE: To analyze retrospectively results of reverse transcription polymerase chain reaction (RT-PCR) testing and demographic information in patients with known or suspected Ewing sarcoma/primitive neuroectodermal tumor family of tumors referred to the National Cancer Institute and to describe factors influencing the determination of molecular marker status. PATIENTS AND METHODS: Tumor samples from 76 patients from February 1997 to December 1999 were analyzed. In all cases, the diagnosis of this family of tumors was confirmed by histopathologic review. RESULTS: In 58 patients, the presence of a translocation associated with this family of tumors was confirmed using RT-PCR. Specifically, there were 45 Ewing sarcoma (EWS)-FLI type 1 translocations, four EWS-FLI type 2 translocations, five EWS-ERG translocations, and four less common EWS-FLI variants. Of patients with a confirmed translocation, four were confirmed only after nested RT-PCR techniques were used. In five patients who initially underwent needle biopsy, the diagnosis was confirmed only after open biopsy or repeat needle biopsy was undertaken. Samples from 18 patients were translocation-negative. Of these, seven samples were deemed inadequate for RT-PCR testing as a result of inappropriate tissue handling or the presence of necrotic material. Five patients were found to have a different diagnosis after complete histopathologic and molecular characterization. Six samples remained, in which adequate tissue was obtained with no evidence of a characteristic translocation. CONCLUSIONS: In apparently translocation-negative samples, close attention should be given to the possibility of an alternative diagnosis, the potential need for nested RT-PCR, and the possibility of an inadequate sample. Strong consideration should be given to the use of open biopsy as opposed to needle biopsy to avoid the need for repeat biopsies and the potential for inaccurate assessment of molecular marker status.

Pediatric oncology: regulatory initiatives.

The majority of children with cancer receive therapy as participants in clinical research protocols coordinated by national pediatric cooperative groups. One of the highest priorities of these groups is the development of novel therapies. Due to differences in the biology of pediatric and adult tumors and in physiology between adults and children, it is usually necessary to evaluate the safety and effectiveness of new drugs separately in adult and pediatric populations. To stimulate the development of new therapies for pediatric indications and encourage the submission of clinical data to support pediatric product labeling, the U.S. Food and Drug Administration has undertaken two initiatives. In 1998 the FDA issued a regulation (The 1998 Final Pediatric Rule) that mandated if a drug or biological is under review for a claim and the disease exists in both pediatric and adult populations, pediatric studies must be performed. Section 111 of the FDA Modernization Act of 1997 states that if a drug product has exclusivity based on a patent or marketing license, the exclusivity can be extended by six months for the submission of pediatric data to the FDA. The incentive applies to both approved drugs and those under development. These initiatives are intended to enhance access to new anticancer therapies and promote labeling for pediatric oncology indications.

Homing and engraftment potential of Sca-1(+)lin(-) cells fractionated on the basis of adhesion molecule expression and position in cell cycle.

Engraftment potential of hematopoietic stem cells (HSCs) is likely to be dependent on several factors including expression of certain adhesion molecules (AMs) and degree of mitotic quiescence. The authors investigated the functional properties and engraftment potential of Sca-1(+)lin(-) cells subfractionated on the basis of expression, or lack thereof, of CD11a, CD43, CD49d, CD49e, or CD62L and correlated that expression with cell cycle status and proliferative potential of engrafting fractions. Donor-derived chimerism in mice receiving CD49e(+) or CD43(+) Sca-1(+)lin(-) cells was greater than that in mice receiving cells lacking these 2 markers, while Sca-1(+)lin(-) cells positive for CD11a and CD62L and bright for CD49d expression mediated minimal engraftment. AM phenotypes enriched for engraftment potential contained the majority of high proliferative potential-colony forming cells, low proliferative potential-colony forming cells, and cells providing rapid in vitro expansion. Cell cycle analysis of AM subpopulations revealed that, regardless of their bone marrow repopulating potential, Sca-1(+)lin(-) AM(-) cells contained a higher percentage of cells in G(0)/G(1) than their AM(+) counterparts. Interestingly, engrafting phenotypes, regardless of the status of their AM expression, were quicker to exit G(0)/G(1) following in vitro cytokine stimulation than their opposing phenotypes. When engrafting phenotypes of Sca-1(+)lin(-) AM(+) or AM(-) cells were further fractionated by Hoechst 33342 into G(0)/G(1) or S/G(2)+M, cells providing long-term engraftment were predominantly contained within the quiescent fraction. These results define a theoretical phenotype of a Sca-1(+)lin(-) engrafting cell as one that is mitotically quiescent, CD43(+), CD49e(+), CD11a(-), CD49d(dim), and CD62L(-). Furthermore, these data suggest that kinetics of in vitro proliferation may be a good predictor of engraftment potential of candidate populations of HSCs. (Blood. 2000;96:1380-1387)

Experimental autoimmune cystitis: further characterization and serum autoantibodies.

Previously, we described an animal model for interstitial cystitis (IC), experimental autoimmune cystitis (EAC) [Luber-Narod et al. Urol Res 24:367]. Further characterization of animals with EAC indicates that peak and mean urinary frequency are elevated compared with sham-injected controls and that the disease progresses with at least two cycles of exacerbations and remissions. We had shown evidence suggesting EAC to be autoimmune in nature. In this paper, we identify serum autoantibodies from 9/10 EAC animals which bind to a protein specific to rat bladder with a relative molecular weight of 12-kDa. Such autoantibodies are absent in 12/13 normal and sham-injected animals as well as animals which fail to develop EAC despite disease induction. These findings suggest that EAC is a reproducible model of cyclical increases of urinary frequency, and that a 12-kDa antigen is the target of autoantibodies which correlate with those elevations. Identification of this target antigen may explain the pathogenesis of increased urinary frequency in these animals and potentially in IC as well.

Rhabdomyosarcoma: an overview.

Rhabdomyosarcoma (RMS) is a malignant tumor of mesenchymal origin thought to arise from cells committed to a skeletal muscle lineage. With approximately 250 cases diagnosed yearly in the United States, it is the third most common extracranial solid tumor of childhood after Wilms' tumor and neuroblastoma. Important epidemiologic, biologic, and therapeutic differences have been elucidated within the RMS family. Common sites of primary disease include the head and neck region, genitourinary tract, and extremities. A site-based tumor-nodes-metastasis staging system is being incorporated into use for assessing prognosis and assigning therapy in conjunction with the traditional surgicopathologic clinical grouping system. The development of intensive multimodality treatment protocols tested in large-scale international trials has resulted in significant improvements in outcome, especially for patients with local or locally extensive disease for whom a 60%-70% disease-free survival can be expected. Despite aggressive approaches incorporating surgery, dose-intensive combination chemotherapy, and radiation therapy, the outcome for patients with metastatic disease remains poor. Future challenges include the development of less toxic therapy for patients with localized disease and new approaches for patients with metastatic disease.

c-Kit and CD38 are expressed by long-term reconstituting hematopoietic cells present in the murine yolk sac.

Murine fetal liver (FL) and adult bone marrow (BM) hematopoietic stem cells (HSCs) are characterized by cell surface expression of CD38 and c-kit. Because murine yolk sac (YS) HSC activity precedes the initiation of FL hematopoiesis, we investigated whether YS-derived HSCs also expressed c-kit and CD38. c-Kit+ CD38+ lineage- cells derived from day 9 YS as well as adult BM were found to be enriched in high proliferative potential colony-forming cells. c-Kit+ CD38+ lineage- YS or adult BM cells were capable of long-term reconstitution (>6 months) of busulfan-conditioned newborn or lethally irradiated adult mice, respectively. In contrast, c-kit+ CD38- lineage- populations from both tissues were enriched in lineage-committed progenitors and had no long-term HSC activity. We concluded that c-kit and CD38 are cell surface markers of HSCs expressed throughout murine ontogeny.

High dose chemotherapy with autologous peripheral blood progenitor cell transplantation in an anephric child with multiply recurrent Wilms tumor.

PURPOSE: An autologous peripheral blood progenitor cell (APBPC) transplant in an anephric child with multiply recurrent Wilms tumor using a conditioning regimen of high dose chemotherapy in conjunction with hemodialysis (HD) and peritoneal dialysis is described. PATIENT AND METHODS: The child had a left nephrectomy at 9 months of age for a stage II Wilms tumor. At 6 years of age, she required a right nephrectomy because of progressive, recurrent disease unresponsive to treatment with doxorubicin, actinomycin, and vincristine. She was maintained on peritoneal dialysis. Salvage chemotherapy consisted of 5 cycles of carboplatin and cyclophosphamide after APBPCs were collected after granulocyte colony-stimulating factor mobilization. After a preparative regimen of carboplatin, cyclophosphamide, and etoposide with closely timed HD, peripheral blood progenitor cells were infused and peritoneal dialysis was resumed. RESULTS: No nonhematopoietic toxicity occurred. Pharmacokinetic studies demonstrated that HD effectively eliminated carboplatin and provided safe, effective plasma concentrations in this anephric patient. Trilineage engraftment occurred by day +10 and the child was discharged from the hospital on day +14. She had a local recurrence on day +194 and died of progressive disease on day +660. CONCLUSIONS: With dialysis support and dose modification, high-dose chemotherapy followed by APBPC transplantation can be successfully performed in the anephric child. Given the lack of organ toxicity in this patient, increased doses of the drugs used in this preparative regimen may be possible for anephric children.