A Six-Gene Signature Predicts Survival of Patients with Localized Pancreatic Ductal Adenocarcinoma

Jen Jen Yeh and colleagues developed and validated a six-gene signature in patients with pancreatic ductal adenocarcinoma that may be used to better stage the disease in these patients and assist in treatment decisions

Valvular regurgitation and surgery associated with fenfluramine use: an analysis of 5743 individuals

<p>Abstract</p> <p>Background</p> <p>Use of fenfluramines for weight loss has been associated with the development of characteristic plaques on cardiac valves causing regurgitation. However, previously published studies of exposure to fenfluramines have been limited by relatively small sample size, short duration of follow-up, and the lack of any estimate of the frequency of subsequent valvular surgery. We performed an observational study of 5743 users of fenfluramines examined by echocardiography between July 1997 and February 2004 in a single large cardiology clinic.</p> <p>Results</p> <p>The prevalence of at least mild aortic regurgitation (AR) or moderate mitral regurgitation (MR) was 19.6% in women and 11.8% in men (<it>p </it>< 0.0001 for gender difference). Duration of use was strongly predictive of mild or greater AR (<it>p </it>< 0.0001 for trend), MR (<it>p </it>= 0.002), and tricuspid regurgitation (TR) (<it>p </it>< 0.0001), as was earlier scan date (<it>p </it>< 0.0001 for those scanned prior to 1 January 2000 versus later). Increasing age was also independently associated with increased risk of AR and MR (both <it>p </it>< 0.0001). With mean follow-up of 30.3 months, AR worsened in 15.2%, remained the same in 63.1%, and improved in 21.7%. Corresponding values for MR were 24.8%, 47.4% and 27.9%. Pulmonary hypertension was strongly associated with MR but not AR. Valve surgery was performed on 38 patients (0.66% of 5743), 25 (0.44%) with clear evidence of fenfluramine-related etiology.</p> <p>Conclusion</p> <p>Regurgitant valvulopathy was common in individuals exposed to fenfluramines, more frequent in females, and associated with duration of use in all valves assessed. Valve surgery was performed as frequently for aortic as mitral valves and some tricuspid valve surgeries were also performed. The incidence of surgery appeared to be substantially increased compared with limited general population data.</p

Decisions that hasten death: double effect and the experiences of physicians in Australia

BACKGROUND: In Australian end-of-life care, practicing euthanasia or physician-assisted suicide is illegal. Despite this, death hastening practices are common across medical settings. Practices can be clandestine or overt but in many instances physicians are forced to seek protection behind ambiguous medico-legal imperatives such as the Principle of Double Effect. Moreover, the way they conceptualise and experience such practices is inconsistent. To complement the available statistical data, the purpose of this study was to understand the reasoning behind how and why physicians in Australia will hasten death. METHOD: A qualitative investigation was focused on palliative and critical/acute settings. A thematic analysis was conducted on semi-structured in-depth interviews with 13 specialist physicians. Attention was given to eliciting meanings and experiences in Australian end-of-life care. RESULTS: Highlighting the importance of a multidimensional approach, physicians negotiated multiple influences when death was regarded as hastened. The way they understood and experienced end-of-life care practices were affected by politico-religious and cultural influences, medico-legal imperatives, and personal values and beliefs. Interpersonal and intrapsychic aspects further emphasised the emotional and psychological investment physicians have with patients and others. In most cases death occurred as a result of treating suffering, and sometimes to fulfil the wishes of patients and others who requested death. Experience was especially subject to the efficacy with which physicians negotiated complex but context-specific situations, and was reflective of how they considered a good death. Although many were compelled to draw on the Principle of Double Effect, every physician reported its inadequacy as a medico-legal guideline. CONCLUSIONS: The Principle of Double Effect, as a simplistic and generalised guideline, was identified as a convenient mechanism to protect physicians who inadvertently or intentionally hastened death. But its narrow focus on the physician’s intent illuminated how easily it may be manipulated, thus impairing transparency and a physician’s capacity for honesty. It is suggested the concept of “force majeure” be examined for its applicability in Australian medical end-of-life law where, consistent with a multidimensional and complex world, a physician’s motivations can also be understood in terms of the emotional and psychological pressures they face in situations that hasten death

Plan Des von einem Theil der Hochfürstlich Hessischen Truppen, unter Höchst eigener Anführung Seiner Hochfürstlichen Durchlaucht des regierenden Herrn Landgraffen Wilhelm IX. zur Sicherheit der Wahlstadt Franckfurth des Churfürstlichen Collegiums, und des zu waehlenden Reichs-Oberhaupts, bezogenen Lagers bey Bergen, und derer daselbst ausgeführten Manoeuvres vom 23ten Septbr. bis 17ten Octbr.1790: aufgenommen und seiner Hochfürstlichen Durchlaucht dem regierenden Herrn Landgraffen Wilhelm IX unterthänigst zugeeignet von H. O. Volmar Capitaine im Artillerie-Regmt. gestochen von J.C.Müller Hoff-Kupferdrucker. o.O.u.J. [nach 1790]

Plan des Lagers der hessischen Truppen unter Landgraf Wilhelm IX bei Bergen vom 23. September bis 17. Oktober 179

Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer's Disease

Alzheimer's disease (AD) is characterized by progressive accumulations of extracellular amyloid-beta (Aβ) aggregates from soluble oligomers to insoluble plaques and hyperphosphorylated intraneuronal tau, also from soluble oligomers to insoluble neurofibrillary tangles (NFTs). Tau and Aβ complexes spread from the entorhinal cortex of the brain to interconnected regions, where they bind pattern recognition receptors on microglia and astroglia to trigger inflammation and neurotoxicity that ultimately lead to neurodegeneration and clinical AD. Systemic inflammation is initiated by Aβ's egress into the circulation, which may be secondary to microglial activation and can confer both destructive and reparative actions. Microglial activation pathways and downstream drivers of Aβ/NFT neurotoxicity, including inflammatory regulators, are primary targets for AD therapy. Osteopontin (OPN), an inflammatory cytokine and biomarker of AD, is implicated in Aβ clearance and toxicity, microglial activation, and inflammation, and is considered to be a potential therapeutic target. Here, using the most relevant works from the literature, we review and contextualize the evidence for a central role of OPN and associated inflammation in AD