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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.

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BACKGROUND: The role of simulation-based education continues to expand exponentially. To excel in this environment as a surgical simulation leader requires unique knowledge, skills, and abilities that are different from those used in traditional clinically-based education. METHODS: Leaders in surgical simulation were invited to participate as discussants in a pre-conference course offered by the Association for Surgical Education. Highlights from their discussions were recorded. RESULTS: Recommendations were provided on topics such as building a simulation team, preparing for accreditation requirements, what to ask for during early stages of development, identifying tools and resources needed to meet educational goals, expanding surgical simulation programming, and building educational curricula. CONCLUSION: These recommendations provide new leaders in simulation with a unique combination of up-to-date best practices in simulation-based education, as well as valuable advice gained from lessons learned from the personal experiences of national leaders in the field of surgical simulation and education.

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Depression is a common outcome for those having experienced early-life stress (ELS). For those individuals, depression typically increases during adolescence and appears to endure into adulthood, suggesting alterations in the development of brain systems involved in depression. Developmentally, the nucleus accumbens (NAcc), a limbic structure associated with reward learning and motivation, typically undergoes dramatic functional change during adolescence; therefore, age-related changes in NAcc function may underlie increases in depression in adolescence following ELS. The current study examined the effects of ELS in 38 previously institutionalized children and adolescents in comparison to a group of 31 youths without a history of ELS. Consistent with previous research, the findings showed that depression was higher in adolescents than children with a history of ELS. Additionally, functional magnetic resonance imaging results showed atypical NAcc development, where the ELS group did not show a typical increase in NAcc reactivity during adolescence. Consequently, the ELS group showed NAcc hypoactivation during adolescence, and lower NAcc reactivity was correlated with higher depression scores. The results have important implications for understanding how ELS may influence increases in depression via neural development during the transition to adolescence and highlight the importance of identifying at-risk individuals in childhood, a potential critical period for depression-targeted intervention.

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Inspired by the hearing organ of the fly Ormia ochracea, a miniature sound localization sensor is developed, which can be used to pinpoint a sound source in two dimensions described by the azimuth and elevation angles. The sensor device employs an equilateral triangle configuration consisting of three mechanically coupled circular membranes whose oscillations are detected by a fiber-optic system. The experimental results indicate that significant amplification of the directional cues and directional sensitivity can be achieved with the fly-ear inspired sensor design. This work can provide a basis for the development of miniature sound localization sensors in two dimensions.

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BACKGROUND: Thoracoscopy and mediastinoscopy are common procedures with painful incisions and prominent scars. A natural orifice transesophageal endoscopic surgical (NOTES) approach could reduce pain, eliminate intercostal neuralgia, provide access to the posterior mediastinal compartment, and improve cosmesis. In addition NOTES esophageal access routes also have the potential to replace conventional thoracoscopic approaches for medial or hilar lesions. METHODS: Five healthy Yorkshire swine underwent nonsurvival natural orifice transesophageal mediastinoscopy and thoracoscopy under general anesthesia. An 8- to 9.8-mm video endoscope was introduced into the esophagus, and a 10-cm submucosal tunnel was created with blunt dissection. The endoscope then was passed through the muscular layers of the esophagus into the mediastinal space. The mediastinal compartment, pleura, lung, mediastinal lymph nodes, thoracic duct, vagus nerves, and exterior surface of the esophagus were identified. Mediastinal lymph node resection was easily accomplished. For thoracoscopy, a small incision was created through the pleura, and the endoscope was introduced into the thoracic cavity. The lung, chest wall, pleura, pericardium, and diaphragmatic surface were identified. Pleural biopsies were obtained with endoscopic forceps. The endoscope was withdrawn and the procedure terminated. RESULTS: Mediastinal and thoracic structures could be identified without difficulty via a transesophageal approach. Lymph node resection was easily accomplished. Pleural biopsy under direct visualization was feasible. Selective mainstem bronchus intubation and collapse of the ipsilateral lung facilitated thoracoscopy. In one animal, an inadvertent 4-mm lung incision resulted in a pneumothorax. This was decompressed with a small venting intercostal incision, and the remainder of the procedure was completed without difficulty. CONCLUSIONS: Transesophageal endoscopic mediastinoscopy, lymph node resection, thoracoscopy, and pleural biopsy are feasible and provide excellent visualization of mediastinal and intrathoracic structures. Survival studies will be needed to confirm the safety of this approach.

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This paper focuses on the evidentiary aspects of the precautionary principle. Three points are highlighted: (i) the difference between association and causation; (ii) how the strength of scientific evidence can be considered; and (iii) the reasons why regulatory regimes tend to err in the direction of false negatives rather than false positives. The point is made that because obtaining evidence of causation can take many decades of research, the precautionary principle can be invoked to justify action when evidence of causation is not available, but there is good scientific evidence of an association between exposures and impacts. It is argued that the appropriate level of proof is context dependent, as "appropriateness" is based on value judgements about the acceptability of the costs, about the distribution of the costs, and about the consequences of being wrong. A complementary approach to evaluating the strength of scientific evidence is to focus on the level of uncertainty. If decision makers are made aware of the limitations of the knowledge base, they can compensate by adopting measures aimed at providing early warnings of un-anticipated effects and mitigating their impacts. The point is made that it is often disregarded that the Bradford Hill criteria for evaluating evidence are asymmetrical, in that the applicability of a criterion increases the strength of evidence on the presence of an effect, but the inapplicability of a criterion does not increase the strength of evidence on the absence of an effect. The paper discusses the reason why there are so many examples of regulatory "false negatives" as opposed to "false positives". Two main reasons are put forward: (i) the methodological bias within the health and environmental sciences; and (ii) the dominance within decision-making of short term economic and political interests. Sixteen features of methods and culture in the environmental and health sciences are presented. Of these, only three features tend to generate "false positives". It is concluded that although the different features of scientific methods and culture produce robust science, they can lead to poor regulatory decisions on hazard prevention.

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Response surface methodology (RSM) was used for controlling molecular weight (MW) and degree of deacetylation (DOD) of chitosan in chemical processing. In a reduced model, MW of chitosan is y = 1736166.406 - 250.745X(1)X(2) - 265.452X(2)X(3), with R( 2) = 0.86, and DOD of chitosan is y = 30.6069 + 0.3396X(1) + 0.4948X(2) + 0.0094X(3)(2), with R( 2) = 0.89. MW of chitosan depends on the crossproduct of temperature and NaOH concentration and the crossproduct of NaOH concentration and time, and DOD depends linearly on temperature and NaOH concentration, and quadratically on time. Chitosan was widely depolymerized in a range from 1,100 kDa to 100 kDa and deacetylated from 67.3 to 95.7% by NaOH alkaline treatment. MW and DOD of chitosan were drastically decreased and increased, respectively, with increase of temperature, reaction time, and NaOH concentration. Furthermore, the rate of MW decrease and DOD increase of chitosan gradually decreased with prolonged reaction time.

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PURPOSE: Despite the importance of culture in health care and the rapid growth of ethnic diversity in the United States and Canada, little is known about the teaching of cultural issues in medical schools. The study goals, therefore, were to determine the number of U.S. and Canadian medical schools that have courses on cultural issues, and to examine the format, content, and timing of those courses. METHOD: The authors contacted the deans of students and/ or directors of courses on cultural issues at all 126 U.S. and all 16 Canadian medical schools. Using a cross-sectional telephone survey, they asked whether each school had a course on cultural sensitivity or multicultural issues and, if so, whether it was separate or contained within a larger course, when in the curriculum the course was taught, and which ethnic groups the course addressed. RESULTS: The response rates were 94% for both U.S. (118) and Canadian (15) schools. Very few schools (U.S. = 8%; and Canada = 0%) had separate courses specifically addressing cultural issues. Schools in both countries usually addressed cultural issues in one to three lectures as part of larger, mostly preclinical courses. Significantly more Canadian than U.S. schools provided no instruction on cultural issues (27% versus 8%; p = .04). Few schools taught about the specific cultural issues of the largest minority groups in their geographic areas: only 28% and 26% of U.S. schools taught about African American and Latino issues, respectively, and only two thirds of Canadian schools taught about either Asian or Native Canadian issues. Only 35% of U.S. schools addressed the cultural issues of the largest minority groups in their particular states. CONCLUSIONS: Most U.S. and Canadian medical schools provide inadequate instruction about cultural issues, especially the specific cultural aspects of large minority groups.

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Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4(+) T cell counts >/= 350 cells/microliter and viral load below the limits of detection for >/=1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies/ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log(10) copies) day(-1), which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log(10) copies) day(-1) (P = 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies/ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4(+) T cells.

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To address the question of how cell turnover is affected by retroviral infections, we used the telomeric terminal restriction fragments (TRFs) as markers of cell replicative history and measured their length in macaques infected with chimeric simian-human immunodeficiency viruses (SHIVs). The TRF lengths of mononuclear cells in 104 samples, including longitudinal samples from nine cynomolgus and ten pig-tailed macaques infected with SHIV, and in samples from 26 uninfected macaques, were quantitated by an improved method, based on two-dimensional calibration of DNA sizes, pulsed field electrophoresis, and high-resolution Southern blot images. The average TRF lengths of peripheral blood mononuclear cells (PBMCs) from uninfected pig-tailed (14.9+/-1.6 kbp) and cynomolgus (14.1+/-1.8 kbp) macaques were about 3 and 5 kbp longer than those of human infants and 30-year-old adults, respectively. The rate of TRF length shortening in infected pig-tailed macaques was significantly (P = 0.035) higher (2.2-fold) than in uninfected monkeys. The TRFs in SHIV-infected cynomolgus monkeys, which, in general, had lower viral loads than pig-tailed macaques, shortened on average more rapidly (1.6-fold) than in uninfected animals, but the difference was not statistically significant. The TRFs of mononuclear cells from the lymph nodes of two rapidly progressing SHIV-infected macaques that developed AIDS and died also shortened in parallel but somewhat more rapidly than in the PBMCs. These results suggest that the rate of PBMC turnover in macaques could be increased several-fold during infections by immunodeficiency viruses, likely due to immune activation by SHIV antigens.

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Telomere shortening may reflect the total number of divisions experienced by a somatic cell and is associated with replicative senescence. We found that the average rate of telomere shortening in peripheral blood mononuclear cells (PBMCs) obtained longitudinally from nine different infants during the first 3 years of life (270 bp per year) is more than fourfold higher than in adults and does not correlate with telomerase activity. These results show that the rate of telomere loss changes during ontogeny, suggesting the existence of periods of accelerated cell division. Because human immunodeficiency virus (HIV) preferentially infects actively dividing cells, our observation suggesting accelerated cell division in children may provide an explanation for some of the distinctive pathogenic features of the HIV disease in infants, including higher viral loads and more rapid progression to acquired immunodeficiency syndrome (AIDS).

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Pulmonary coccidioidomycosis is a rare cause of pulmonary nodules and respiratory infection in travellers to endemic areas. An Australian tourist suffered an acute respiratory illness while on holiday in Mexico. She subsequently developed erythema nodosum and was noted to have a left pulmonary nodule on chest X-ray after return to Australia. The diagnosis of Coccidioides immitis infection was established by histology and culture of the resected lung lesion. The patient made an uneventful recovery and received one month of therapy with ketoconazole. Culture of the fungus took place under controlled Class 3 conditions. An unusual fungal infection in Australia, coccidioidomycosis poses special risks to staff of microbiology laboratories.

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To quantify the long-term dynamics of telomere lengths and the effect of HIV infection on lymphocyte turnover rates, we measured in a blinded study longitudinal samples from 6 individuals using a highly accurate method based on two-dimensional calibration of DNA sizes. For two uninfected controls followed 8 and 10 years the average telomeric terminal restriction fragment (TRF) shortening rate in peripheral blood mononuclear cells (PBMCs) was 50 and 60 bp/year, respectively, in agreement with previous measurements of cross-sectional samples. The TRF lengths of PBMCs from two slow progressors followed for 14 years declined by a rate of 120 +/-10 bp/year, i.e. 2-fold higher than the rate of TRF shortening for uninfected individuals. The rate of TRF shortening was higher in CD8 (140 +/-10 bp/year) than in CD4 (100 +/-10 bp/year) cells. The CD8 cell TRFs of the two fast progressors shortened faster (240 +/-10 bp/year) and the rate of CD4 cell TRF shortening in one of the fast progressors was 160 bp/year. These data suggest that HIV infection causes only a modest increase in the lymphocyte turnover which we speculate could be due to chronic activation of the immune system, and may not result in the exhaustion of its regenerative capacity and immunopathogenesis.

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We developed an improved method for accurately measuring telomere lengths based on two-dimensional calibration of DNA sizes combined with pulsed field electrophoresis and quantitative analysis of high-resolution gel images. This method was used to quantify the length of telomeres in longitudinal samples of peripheral blood mononuclear cells (PBMCs) from five chimpanzees infected with human immunodeficiency virus type 1 (HIV-1) and three uninfected animals, 14 to 27 years of age. The average length of the telomere restriction fragments (TRF) of infected and uninfected chimpanzees were 11.7 +/- 0.25 kbp, and 11.6 +/- 0.61 kbp, respectively, and were about 1 kbp and 3 kbp longer than those of human infants and 30 year old adults, respectively. There was a trend of a slight decrease (30-60 bp per year) in the TRF of two HIV infected chimpanzees over 30-35 months, while the TRF of one naive chimpanzee slightly increased over 20 months. Although the number of chimpanzees in this study is small and no statistically significant linear dependencies on time were observed, it appears that in chimpanzees, rates of shortening of the TRF are comparable or smaller than in adult humans and are not significantly affected by HIV-1 infection, which may be related to the inability of HIV-1 to cause disease in these animals.

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OBJECTIVE: To identify whether and how family physicians practising home care resolve ethical dilemmas in clinical management of homebound patients and to examine whether the self-reported, theoretical ethical positions of these physicians match their actual patient management. DESIGN: Cross-sectional survey. SETTING: Quebec community-based home care program. PARTICIPANTS: Quebec family physicians actively involved in community-based home care: 85 men and 65 women. MAIN OUTCOME MEASURES: Physician level of agreement with theoretical ethical statements about autonomy, caregiver needs, and resource allocation; management options chosen for a clinical case vignette; and mechanisms used for resolving conflicts. RESULTS: There were 209 respondents to the 279 questionnaires sent (75%). Of these, 59 who were not currently involved in home care were excluded, leaving 150 participants. Most (83.3%) physicians surveyed agreed with the ethical principle of patient autonomy; 88.7% agreed that the interests of family caregivers are important in decisions regarding patients, and 72.0% agreed that limiting home care services is reasonable in the context of limited resources. In managing a patient, 65.3% of physicians thought the patient should be placed in a nursing home against her wishes because of "danger to self," while 82.7% felt she should be placed if the caregiver is "exhausted." Three quarters of physicians did not limit or decrease home care services, despite noncompliance. CONCLUSIONS: Family physicians practising community-based home care in Quebec have practical views on various ethical principles guiding home care practice. Except in the area of limiting or discontinuing home care services, their ethical framework is reflected in a case vignette of patient management.

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The death of a prisoner in the Tower of London in 1585 is reviewed from the point of view of a modern forensic pathologist, and explanations for the death are suggested.

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Activated protein C (APC) is a highly specific serine proteinase which functions as an important naturally occurring antithrombotic enzyme. APC also has anti-inflammatory properties. We have developed a large-scale process for the production of APC for therapeutic use starting with cryoprecipitate-poor human plasma. This report describes the process, its performance at the pilot plant scale, and the characteristics of immunoaffinity-purified human APC concentrate referred to as APC (human). The process consists of three chromatographic steps, an enzymatic conversion step, and incorporates a solvent/detergent treatment step for the inactivation of lipid-enveloped viruses. Solvent/detergent was shown to rapidly inactivate spiked HIV-1, as well as three marker viruses to nondetectable levels under process conditions. The immunoaffinity-purified protein C (PC) intermediate was enriched 13,600-fold over plasma and had a specific activity of 231 U/mg. The overall yield of the process following enzymatic conversion of the PC intermediate to APC and its processing by anion exchange chromatography was 36%. APC (human) was shown to be highly purified, functional and stable.

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A second-derivative scan of an acidified urine sample allows the amplitude of deflection (delta A) and the minimum wavelength of the trough (lambda min) to determine the correct porphyrin concentration and the coproporphyrin:uroporphyrin (copro:uro) ratio, respectively, from a nomogram constructed from calibrator solutions. We measured 24 urine samples for total porphyrin as coproporphyrin equivalents and adjusted the results with factors from the nomogram. The adjusted results (x) (mean +/- SE, 501 +/- 57 nmol/L) compared favorably with the expected results (y) (514 +/- 57). The regression equation and correlation coefficient were: y = 0.993x - 8.9 (r = 0.998, S(y/x) = 16.2). Results of the copro:uro ratio derived by second-derivative spectroscopy and HPLC showed no significant difference (chi 2-test) from samples with various copro:uro ratios. Recovery studies on four urine samples supplemented with known proportions of coproporphyrins and uroporphyrins gave good agreement between the measured and the expected porphyrin ratios. The overall imprecision (CV) of the assay ranged from 3.6% to 6.0% for coproporphyrin and from 3.2% to 9.1% for uroporphyrin.

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