Current Dyspnea Among Long-Term Survivors of Early-Stage Non-small Cell Lung Cancer

IntroductionDyspnea is common among lung cancer patients. As most studies of dyspnea have reviewed patients with active cancer or immediately after treatment, its prevalence during the longer-term period once treatment has been completed is not well characterized. This study quantifies the prevalence of dyspnea among lung cancer survivors and identifies potential correlates that may be amenable to intervention.MethodsCross-sectional survey of 342 patients with disease-free, stage I, non-small cell lung cancer, assessed 1 to 6 years after surgical resection. Dyspnea was quantified using the Baseline Dyspnea Index. Any moderate/strenuous physical activity was measured using the Godin Leisure-Time Exercise Questionnaire. Mood disorder symptoms were assessed using the Hospital Anxiety and Depression Scale. Multiple regression analyses were used to examine demographic, medical, and health-related correlates of dyspnea.ResultsMean age was 68.9 years. Average predicted preoperative forced expiratory volume in 1 second was 89.0%. Current dyspnea, defined by a Baseline Dyspnea Index score of 9 or less, existed among 205 (60%) individuals. For 133 (65%) of these patients, dyspnea was absent preoperatively. Multivariate correlates of current dyspnea included preoperative dyspnea (odds ratio [OR] = 5.31), preoperative diffusing capacity (OR = 0.98), lack of moderate/strenuous physical activity (OR = 0.41), and the presence of clinically significant depression symptoms (OR = 4.10).ConclusionsDyspnea is common 1 to 6 years after lung cancer resection, and is associated with the presence of preoperative dyspnea, reduced diffusing capacity, clinically significant depression symptoms, and lack of physical activity. Further research is needed to test whether strategies that identify and treat patients with these conditions attenuate dyspnea among lung cancer survivors

Essentially English : Sherlock Holmes at the BBC

Sir Arthur Conan Doyle’s Sherlock Holmes stories, currently enjoying renewed popularity on television via the BBC’s Sherlock (2010- ), have been adapted for the screen countless times around the world. Arguably best remembered are Granada’s long-running strand with Jeremy Brett (1984-94), and the Universal film series of the 1940s, featuring Basil Rathbone and Nigel Bruce. Less frequently cited, however, are the two series produced by the BBC between 1965 and 1968, in which first Douglas Wilmer and later Peter Cushing took on the mantle of the Baker Street detective. Typically for the time – but against the wishes of the Conan Doyle estate - these programmes adopted a multi-camera studio model; a mode of production which made them less attractive to US networks than the single camera 35mm film output of commercial rivals such as ITC. Drawing upon material from the BBC’s Written Archives Centre, this article investigates the motivations underpinning the Corporation’s refusal to accommodate the estate’s exhortations to seek American co-production and utilise single camera filming, not least of which was the BBC’s stated desire to maintain the ‘essentially English’ quality of Sherlock Holmes. This decision would have significant repercussions for the series’ overseas saleability, and – despite impressive viewing figures and positive audience reaction at home in the UK – helped contribute to its ‘forgotten’ status with regard to the television canon

Candidate X-ray-Emitting OB Stars in the Carina Nebula Identified Via Infrared Spectral Energy Distributions

We report the results of a new survey of massive, OB stars throughout the Carina Nebula using the X-ray point source catalog provided by the Chandra Carina Complex Project (CCCP) in conjunction with infrared (IR) photometry from the Two Micron All-Sky Survey and the Spitzer Space Telescope Vela--Carina survey. Mid-IR photometry is relatively unaffected by extinction, hence it provides strong constraints on the luminosities of OB stars, assuming that their association with the Carina Nebula, and hence their distance, is confirmed. We fit model stellar atmospheres to the optical (UBV) and IR spectral energy distributions (SEDs) of 182 OB stars with known spectral types and measure the bolometric luminosity and extinction for each star. We find that the extinction law measured toward the OB stars has two components: Av=1--1.5 mag produced by foreground dust with a ratio of total-to-selective absorption Rv=3.1 plus a contribution from local dust with Rv>4.0 in the Carina molecular clouds that increases as Av increases. Using X-ray emission as a strong indicator of association with Carina, we identify 94 candidate OB stars with Lbol\geq10^4 Lsun by fitting their IR SEDs. If the candidate OB stars are eventually confirmed by follow-up spectroscopic observations, the number of cataloged OB stars in the Carina Nebula will increase by ~50%. Correcting for incompleteness due to OB stars falling below the Lbol cutoff or the CCCP detection limit, these results potentially double the size of the young massive stellar population.Comment: 19 pages, 8 figures, accepted for the ApJS Special Issue on the Chandra Carina Complex Project (CCCP), scheduled for publication in May 2011. All 16 CCCP Special Issue papers, including a version of this article with high-quality figures, are available at http://cochise.astro.psu.edu/Carina_public/special_issue.html (through 2011 at least

Ischaemic strokes in patients with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia: associations with iron deficiency and platelets.

<div><p>Background</p><p>Pulmonary first pass filtration of particles marginally exceeding ∼7 µm (the size of a red blood cell) is used routinely in diagnostics, and allows cellular aggregates forming or entering the circulation in the preceding cardiac cycle to lodge safely in pulmonary capillaries/arterioles. Pulmonary arteriovenous malformations compromise capillary bed filtration, and are commonly associated with ischaemic stroke. Cohorts with CT-scan evident malformations associated with the highest contrast echocardiographic shunt grades are known to be at higher stroke risk. Our goal was to identify within this broad grouping, which patients were at higher risk of stroke.</p><p>Methodology</p><p>497 consecutive patients with CT-proven pulmonary arteriovenous malformations due to hereditary haemorrhagic telangiectasia were studied. Relationships with radiologically-confirmed clinical ischaemic stroke were examined using logistic regression, receiver operating characteristic analyses, and platelet studies.</p><p>Principal Findings</p><p>Sixty-one individuals (12.3%) had acute, non-iatrogenic ischaemic clinical strokes at a median age of 52 (IQR 41–63) years. In crude and age-adjusted logistic regression, stroke risk was associated not with venous thromboemboli or conventional neurovascular risk factors, but with low serum iron (adjusted odds ratio 0.96 [95% confidence intervals 0.92, 1.00]), and more weakly with low oxygen saturations reflecting a larger right-to-left shunt (adjusted OR 0.96 [0.92, 1.01]). For the same pulmonary arteriovenous malformations, the stroke risk would approximately double with serum iron 6 µmol/L compared to mid-normal range (7–27 µmol/L). Platelet studies confirmed overlooked data that iron deficiency is associated with exuberant platelet aggregation to serotonin (5HT), correcting following iron treatment. By MANOVA, adjusting for participant and 5HT, iron or ferritin explained 14% of the variance in log-transformed aggregation-rate (p = 0.039/p = 0.021).</p><p>Significance</p><p>These data suggest that patients with compromised pulmonary capillary filtration due to pulmonary arteriovenous malformations are at increased risk of ischaemic stroke if they are iron deficient, and that mechanisms are likely to include enhanced aggregation of circulating platelets.</p></div

Hypoplastic Left Heart Syndrome Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients

Dealing with heterogeneity of treatment effects: is the literature up to the challenge?

<p>Abstract</p> <p>Background</p> <p>Some patients will experience more or less benefit from treatment than the averages reported from clinical trials; such variation in therapeutic outcome is termed heterogeneity of treatment effects (HTE). Identifying HTE is necessary to individualize treatment. The degree to which heterogeneity is sought and analyzed correctly in the general medical literature is unknown. We undertook this literature sample to track the use of HTE analyses over time, examine the appropriateness of the statistical methods used, and explore the predictors of such analyses.</p> <p>Methods</p> <p>Articles were selected through a probability sample of randomized controlled trials (RCTs) published in <it>Annals of Internal Medicine</it>, <it>BMJ</it>, <it>JAMA</it>, <it>The Lancet</it>, and <it>NEJM </it>during odd numbered months of 1994, 1999, and 2004. RCTs were independently reviewed and coded by two abstractors, with adjudication by a third. Studies were classified as reporting: (1) HTE analysis, utilizing a formal test for heterogeneity or treatment-by-covariate interaction, (2) subgroup analysis only, involving no formal test for heterogeneity or interaction; or (3) neither. Chi-square tests and multiple logistic regression were used to identify variables associated with HTE reporting.</p> <p>Results</p> <p>319 studies were included. Ninety-two (29%) reported HTE analysis; another 88 (28%) reported subgroup analysis only, without examining HTE formally. Major covariates examined included individual risk factors associated with prognosis, responsiveness to treatment, or vulnerability to adverse effects of treatment (56%); gender (30%); age (29%); study site or center (29%); and race/ethnicity (7%). Journal of publication and sample size were significant independent predictors of HTE analysis (p < 0.05 and p < 0.001, respectively).</p> <p>Conclusion</p> <p>HTE is frequently ignored or incorrectly analyzed. An iterative process of exploratory analysis followed by confirmatory HTE analysis will generate the data needed to facilitate an individualized approach to evidence-based medicine.</p

Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Novel variants in the PRDX6 Gene and the risk of Acute Lung Injury following major trauma

<p>Abstract</p> <p>Background</p> <p>Peroxiredoxin 6 (<it>PRDX6</it>) is involved in redox regulation of the cell and is thought to be protective against oxidant injury. Little is known about genetic variation within the PRDX6 gene and its association with acute lung injury (ALI). In this study we sequenced the <it>PRDX6 </it>gene to uncover common variants, and tested association with ALI following major trauma.</p> <p>Methods</p> <p>To examine the extent of variation in the <it>PRDX6 </it>gene, we performed direct sequencing of the 5' UTR, exons, introns and the 3' UTR in 25 African American cases and controls and 23 European American cases and controls (selected from a cohort study of major trauma), which uncovered 80 SNPs. <it>In silico </it>modeling was performed using Patrocles and Transcriptional Element Search System (TESS). Thirty seven novel and tagging SNPs were tested for association with ALI compared with ICU at-risk controls who did not develop ALI in a cohort study of 259 African American and 254 European American subjects that had been admitted to the ICU with major trauma.</p> <p>Results</p> <p>Resequencing of critically ill subjects demonstrated 43 novel SNPs not previously reported. Coding regions demonstrated no detectable variation, indicating conservation of the protein. Block haplotype analyses reveal that recombination rates within the gene seem low in both Caucasians and African Americans. Several novel SNPs appeared to have the potential for functional consequence using <it>in silico </it>modeling. Chi²analysis of ALI incidence and genotype showed no significant association between the SNPs in this study and ALI. Haplotype analysis did not reveal any association beyond single SNP analyses.</p> <p>Conclusions</p> <p>This study revealed novel SNPs within the <it>PRDX6 </it>gene and its 5' and 3' flanking regions via direct sequencing. There was no association found between these SNPs and ALI, possibly due to a low sample size, which was limited to detection of relative risks of 1.93 and above. Future studies may focus on the role of <it>PRDX6 </it>genetic variation in other diseases, where oxidative stress is suspected.</p