Technical Report Value of Systems Engineering

This report is a follow-on from the June 2004 Air Force/Lean Aerospace Initiative Workshop on Systems Engineering for Robustness

Identification of neuroactive steroids and their precursors and metabolites in adult male rat brain

Steroids in the brain arise both from local synthesis and from peripheral sources and have a variety of effects on neuronal function. However, there is little direct chemical evidence for the range of steroids present in brain or of the pathways for their synthesis and inactivation. This information is a prerequisite for understanding the regulation and function of brain steroids. After extraction from adult male rat brain, we have fractionated free steroids and their sulfate esters and then converted them to heptafluorobutyrate or methyloxime-trimethylsilyl ether derivatives for unequivocal identification and assay by gas chromatography analysis and selected ion monitoring mass spectrometry. In the free steroid fraction, corticosterone, 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone, testosterone, and dehydroepiandrosterone were found in the absence of detectable precursors usually found in endocrine glands, indicating peripheral sources and/or alternative synthetic pathways in brain. Conversely, the potent neuroactive steroid 3 alpha, 5 alpha-tetrahydroprogesterone ( allopregnanolone) was found in the presence of its precursors pregnenolone, progesterone, and 5 alpha-dihydroprogesterone. Furthermore, the presence of 3 alpha-, 11 alpha-, 17 alpha-, and 20 alpha-hydroxylated metabolites of 3 alpha, 5 alpha-tetrahydroprogesterone implicated possible inactivation pathways for this steroid. The 20 alpha-reduced metabolites could also be found for pregnenolone, progesterone, and 5 alpha-dihydroprogesterone, introducing a possible regulatory diversion from the production of 3 alpha, 5 alpha-tetrahydroprogesterone. In the steroid sulfate fraction, dehydroepiandrostrone sulfate was identified but not pregnenolone sulfate. Although pharmacologically active, identification of the latter appears to be an earlier methodological artifact, and the compound is thus of doubtful physiological significance in the adult brain. Our results provide a basis for elucidating the origins and regulation of brain steroids

Assessing the level of healthcare information technology adoption in the United States: a snapshot

BACKGROUND: Comprehensive knowledge about the level of healthcare information technology (HIT) adoption in the United States remains limited. We therefore performed a baseline assessment to address this knowledge gap. METHODS: We segmented HIT into eight major stakeholder groups and identified major functionalities that should ideally exist for each, focusing on applications most likely to improve patient safety, quality of care and organizational efficiency. We then conducted a multi-site qualitative study in Boston and Denver by interviewing key informants from each stakeholder group. Interview transcripts were analyzed to assess the level of adoption and to document the major barriers to further adoption. Findings for Boston and Denver were then presented to an expert panel, which was then asked to estimate the national level of adoption using the modified Delphi approach. We measured adoption level in Boston and Denver was graded on Rogers' technology adoption curve by co-investigators. National estimates from our expert panel were expressed as percentages. RESULTS: Adoption of functionalities with financial benefits far exceeds adoption of those with safety and quality benefits. Despite growing interest to adopt HIT to improve safety and quality, adoption remains limited, especially in the area of ambulatory electronic health records and physician-patient communication. Organizations, particularly physicians' practices, face enormous financial challenges in adopting HIT, and concerns remain about its impact on productivity. CONCLUSION: Adoption of HIT is limited and will likely remain slow unless significant financial resources are made available. Policy changes, such as financial incentivesto clinicians to use HIT or pay-for-performance reimbursement, may help health care providers defray upfront investment costs and initial productivity loss

“Working the System”—British American Tobacco's Influence on the European Union Treaty and Its Implications for Policy: An Analysis of Internal Tobacco Industry Documents

Katherine Smith and colleagues investigate the ways in which British American Tobacco influenced the European Union Treaty so that new EU policies advance the interests of major corporations, including those that produce products damaging to health

Todas as criaturas do mundo: a arte dos mapas como elemento de orientação geográfica

Vague in the outlines and abounding in figures of real or fabulous creatures, the iconography of medieval maps played a significant role in helping users to recognize lands that were virtually unknown to Christendom. In a world with no reliable latitudes and longitudes, the land contours, inhabitants and even certain elements of fauna and flora could become variables of utmost importance for geographic orientation. Notwithstanding the higher levels of precision achieved in their efforts to represent geographic space, the considerable advancements made in latitude determination, and their continuous pursuit of a practical method for the establishment of longitudes, the cartographers of the Age of Discoveries still went to the trouble of depicting notable elements - whether real or imaginary - to help travelers get their bearings around different regions of the globe. As the presence of Europeans continued to expand and an authentic scientific revolution took place in the 17th century, the lengthy notes and eye¿catching representations of nature and local inhabitants soon lost their utility as points of reference on 17th-century maps to become mere accessories of aesthetic and commercial value. The advent of the 18th century consolidated, once and for all, the transformation of such illustrations into essentially decorative elements with no other relevant role to play in mapmaking. In addition to decreasing in number, the figures became more stylized and moved to the borders of the maps as ornamental motifs. Although they often maintained some sort of relation with the geographic space depicted on the map, the motifs chosen could also constitute a rather independent element. In fact, allegories, compositions with a variety of mythological figures, and historical representations were often used to underscore the power of certain political agents

Session 17 Ecophysiology

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Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

The SARS-CoV-2 Alpha variant was associated with increased clinical severity of COVID-19 in Scotland: A genomics-based retrospective cohort analysis

Objectives The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this. Methods In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death. Results Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants). Conclusions The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages