tbuckley/cabot-search huggingface dataset:
Effect of the Statistical Significance of Results on the Time to Completion and Publication of Randomized Efficacy Trials
Authors: John P. A. Ioannidis
Journal: JAMA (1998)

Context.—Medical evidence may be biased over time if completion and publication of randomized efficacy trials are delayed when results are not statistically significant.Objective.—To evaluate whether the time to completion and the time to publication of randomized phase 2 and phase 3 trials are affected by the statistical significance of results and to describe the natural history of such trials.Design.—Prospective cohort of randomized efficacy trials conducted by 2 trialist groups from 1986 to 1996.Setting.—Multicenter trial groups in human immunodeficiency virus infection sponsored by the National Institutes of Health.Patients.—A total of 109 efficacy trials (total enrollment, 43708 patients).Main Outcome Measures.—Time from start of enrollment to completion of follow-up and time from completion of follow-up to peer-reviewed publication assessed with survival analysis.Results.—The median time from start of enrollment to publication was 5.5 years and was substantially longer for negative trials than for results favoring an experimental arm (6.5 vs 4.3 years, respectively; P&lt;.001; hazard ratio for time to publication for positive vs negative trials, 3.7; 95% confidence interval [CI], 1.8-7.7). This difference was mostly attributable to differences in the time from completion to publication (median, 3.0 vs 1.7 years for negative vs positive trials; P&lt;.001). On average, trials with significant results favoring any arm completed follow-up slightly earlier than trials with nonsignificant results (median, 2.3 vs 2.5 years; P=.045), but long-protracted trials often had low event rates and failed to reach statistical significance, while trials that were terminated early had significant results. Positive trials were submitted for publication significantly more rapidly after completion than were negative trials (median, 1.0 vs 1.6 years; P=.001) and were published more rapidly after submission (median, 0.8 vs 1.1 years; P=.04).Conclusion.—Among randomized efficacy trials, there is a time lag in the publication of negative findings that occurs mostly after the completion of the trial follow-up.
Doctors and manslaughter--response from the Crown Prosecution Service
Authors: S. O'Doherty
Journal: Journal of the Royal Society of Medicine (2006)

In an article published in the JRSM, Volume 99, Ferner and McDowell adopted a literature review of doctors charged with manslaughter since 1795.From a reading of their article it is possible to determine that they arrived at the following conclusions.First, that there had been a significant increase in the prosecution of doctors for gross negligence manslaughter since 1990; second, that the majority of these doctors should not have been prosecuted; third, that the Crown Prosecution Service (CPS) has failed to abide by its own prosecution Code; and fourth, that we have charged doctors as 'an emotionally satisfying way to exact retribution . . .'We question the methodology, analysis and conclusions reached by the authors.They relied for the most part on newspaper reports, a notoriously unreliable source, for an accurate account of the allegations.In every case all the evidence is considered by experienced doctors before any prosecution is commenced.We apply the criminal law on gross negligence manslaughter as we are required to do, yet Ferner and McDowell criticise us for not using the criteria of 'mistakes, slips (or lapses) and violations', tests that are unknown to the criminal law.Ferner and McDowell have failed to understand the CPS 'realistic prospect of conviction' test and have applied a simplistic numerical test against all the cases they could identify.The test is whether in this particular case there is a realistic prospect of conviction, not whether half of all defendants are convicted.The suggestion that, by charging doctors with manslaughter, the CPS is somehow seeking some emotional satisfaction in retribution is self-evidently bizarre and entirely unsupported by any evidence.
Erratum to “Long-term mortality after Staphylococcus aureus spondylodiscitis: A Danish nationwide population-based cohort study” [J Infect 69 (2014) 252–258]
Authors: Theis Aagaard, Casper Roed, Anders R. Larsen, Andreas Petersen, Benny Dahl, Peter Skinhøj, Niels Obel
Journal: Journal of Infection (2014)
mTORC 2:1 for Chemotherapy Sensitization in Glioblastoma
Authors: Wolfgang Wick, Jonas Blaes, Markus Weiler
Journal: Cancer Discovery (2011)

Abstract mTOR signaling is frequently deregulated in cancer, including brain tumors. Although the signaling of mTOR complex 1 (mTORC1) has been subject to intensive investigations and mTORC1 itself has been a well-established cancer drug target for years, the role of the second complex, mTORC2, remains elusive. Tanaka et al. reveal an EGFRvIII-mTORC2-NFκB signaling cascade and demonstrate that mTORC2 mediates cisplatin resistance through NF-κB in an Akt-independent manner in glioblastoma. Uncovering the role of mTORC2 in chemotherapy resistance in glioblastoma highlights the need for further investigations of mTORC2 inhibition. Cancer Discovery; 1(6); 475–76. ©2011 AACR. Commentary on Tanaka et al., p. 524.
Bacteria and mould components in house dust and children's allergic sensitisation
Authors: U. Gehring, J. Heinrich, G. Hoek, M. Giovannangelo, E. Nordling, T. Bellander, J. Gerritsen, J. C. de Jongste, H. A. Smit, H-E. Wichmann, M. Wickman, B. Brunekreef
Journal: European Respiratory Journal (2007)

It has been suggested that early childhood exposure to microbial agents decreases the risk of allergies in children. The current authors studied the association between microbial agents in house dust and allergic sensitisation in children aged 2–4 yrs. Nested case-control studies were performed within ongoing birth cohort studies in Germany, the Netherlands and Sweden and ∼180 sensitised and 180 nonsensitised children were selected per country. Levels of bacterial endotoxin, β(1,3)-glucans and fungal extracellular polysaccharides (EPS) were measured in dust samples from the children’s mattresses and the living-room floors. Combined across countries, higher amounts of mattress dust and higher mattress dust loads of endotoxin, β(1,3)-glucans and EPS were associated with a significantly decreased risk of sensitisation to inhalant allergens. After mutual adjustment, only the protective effect of the amount of mattress dust remained significant (odds ratio (95% confidence interval) 0.57(0.39–0.84)). Higher amounts of mattress dust may decrease the risk of allergic sensitisation to inhalant allergens. The effect might be partly attributable to endotoxin, β(1,3)-glucans and extracellular polysaccharides, but could also reflect (additional) protective effects of (microbial) agents other than the ones measured. It is not possible to distinguish with certainty which component relates to the effect, since their levels are highly correlated.
Diverging trends in incidence and mortality, and improved survival of non-Hodgkin's lymphoma, in the Netherlands, 1989–2007
Authors: S.A.M. van de Schans, D.E. Issa, O. Visser, P. Nooijen, P.C. Huijgens, H.E. Karim-Kos, M.L.G. Janssen-Heijnen, J.W.W. Coebergh
Journal: Annals of Oncology (2011)
Meningococcal disease and its management in children
Authors: C Anthony Hart, Alistair P J Thomson
Journal: BMJ (2006)

Meningococcal disease produces a considerable global burden of disease. In this clinical review we focus mainly on meningococcal disease in the United Kingdom, but we also acknowledge the wider issues across the world. Meningococcal disease, which may present clinically as septicaemia, as meningitis, or with a mixed picture, is caused by infection with Neisseria meningitidis or meningococcus.

Recent advances include greater knowledge about the pathogenesis of meningococcal disease, work to facilitate its early diagnosis, and some evidence of improved outcomes after meningococcal disease. Despite these advances, valid evidence from large controlled studies is scarce, so most recommendations are based on consensus or tradition rather than on firm scientific evidence.

Description of the disease only as “meningitis” is inaccurate and misleading to patients and professionals. Septicaemia is the more dangerous clinical syndrome,1 which needs urgent treatment; meningitis also needs rapid treatment but is more likely to lead to neurodevelopmental sequelae. In the meningitis belt of sub-Saharan Africa, meningococcal disease presents predominantly as meningitis alone.2

### What causes it

The meningococcus is solely a human pathogen, and up to 50% of the population may carry meningococci in the nasopharynx.3 w1 Factors that lead to invasion and production of disease include complex inter-relationships of genetic predisposition, host status, environmental conditions, and virulence of the organism.4 w2

### Literature searches

We searched Medline in May 2006 (PubMed, since 1966, except where stated) with the terms meningococcus, meningococcal infection, meningococcal disease, meningococcal disease and predisposition (English, reviews, past 5 years), meningococcal disease and carriage (English, reviews, past 5 years), meningococcal disease and symptoms, meningococcal disease and signs, meningococcal disease and treatment, meningococcal disease and outcome, and meningococcal disease and prevention. We also did a Google search, which found about 2.5 million references on meningococcal disease

### Summary points

Meningococcal disease is the most common infectious cause of death in childhood in …
Genomic Sequencing for Cancer Diagnosis and Therapy
Authors: Linghua Wang, David A. Wheeler
Journal: Annual Review of Medicine (2013)

For a decade, the technologies behind DNA sequencing have improved rapidly in cost reduction and speed. Sequencing in large populations of cancer patients is leading to dramatic advances in our understanding of the cancer genome. The wide variety of cancer types sequenced and analyzed using these technologies has revealed many novel fundamental genetic mechanisms driving cancer initiation, progression, and maintenance. We have deepened our understanding of the signaling pathways, demonstrating disruption in epigenetic regulation and destabilization of the splicing machinery. The molecular mechanisms of resistance to targeted therapies are being elucidated for the first time. The translation of genome-scale variation into clinically actionable information is still in its infancy; nevertheless, insights from sequencing studies have led to the discovery of a variety of novel diagnostic biomarkers and therapeutic targets. Here, we review recent advances in cancer genomics and discuss what the new findings have taught us about cancer biology and, more importantly, how these new findings guide more effective diagnostic and treatment strategies.
Investigation of Mammographic Breast Density as a Risk Factor for Ovarian Cancer
Authors: K. J. Wernli, E. S. O'Meara, K. Kerlikowske, D. L. Miglioretti, C. Y. Muller, T. Onega, B. L. Sprague, L. M. Henderson, D. S. M. Buist
Journal: JNCI Journal of the National Cancer Institute (2013)

Endogenous hormones and growth factors that increase mammographic breast density could increase ovarian cancer risk. We examined whether high breast density is associated with ovarian cancer risk. We conducted a cohort study of 724603 women aged 40 to 79 years with 2506732 mammograms participating in the Breast Cancer Surveillance Consortium from 1995 to 2009. Incident epithelial ovarian cancer was diagnosed in 1373 women. We used partly conditional Cox regression to estimate the association between breast density and 5-year risk of incident epithelial ovarian cancer overall and stratified by 10-year age group. All statistical tests were two-sided. Compared with women with scattered fibroglandular densities, women with heterogeneously dense and extremely dense breast tissue had 20% and 18% increased 5-year risk of incident epithelial ovarian cancer (hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 1.06 to 1.36; HR = 1.18, 95% CI = 0.93 to 1.50, respectively; Ptrend = .01). Among women aged 50 to 59 years, we observed a trend in elevated risk associated with increased breast density ( Ptrend = .02); women with heterogeneously and extremely dense breast tissue had 30% (HR = 1.30; 95% CI = 1.03 to 1.64) and 65% (HR = 1.65; 95% CI = 1.12 to 2.44) increased risk, respectively, compared with women with scattered fibroglandular densities. The pattern was similar but not statistically significant at age 40 to 49 years. There were no consistent patterns of breast density and ovarian cancer risk at age 60 to 79 years. Dense breast tissue was associated with a modest increase in 5-year ovarian cancer risk in women aged 50 to 59 years but was not associated with ovarian cancer at ages 40 to 49 or 60 to 79 years.
Silencing of SPRY1 Triggers Complete Regression of Rhabdomyosarcoma Tumors Carrying a Mutated <i>RAS</i> Gene
Authors: Gerben Schaaf, Mohamed Hamdi, Danny Zwijnenburg, Arjan Lakeman, Dirk Geerts, Rogier Versteeg, Marcel Kool
Journal: Cancer Research (2010)

Abstract RAS oncogenes are among the most frequently mutated genes in human cancer, but effective strategies for therapeutic inhibition of the RAS pathway have been elusive. Sprouty1 (SPRY1) is an upstream antagonist of RAS that is activated by extracellular signal-related kinase (ERK), providing a negative feedback loop for RAS signaling, and other evidence suggests that SPRY1 may have a tumor suppressor function. Studies of RAS status in the human childhood tumor rhabdomyosarcoma (RMS) indicated mutations in approximately half of the tumors of the embryonal rhabdomyosarcoma subtype (ERMS) but not the alveolar subtype (ARMS). ERMS tumors also showed overexpression of SPRY1, which was indeed upregulated by mutant RAS. However, we found that, in the presence of mutant RAS, the function of SPRY1 was changed from an antagonist to an agonist of RAS signaling. Thus, SPRY1 supported formation of activated ERK and mitogen-activated protein/ERK kinase and was essential for ERMS cell proliferation and survival. Conversely, silencing of SPRY1 in ERMS cells (but not ARMS cells) abolished their tumorigenicity in mice. Moreover, silencing of SPRY1 caused regression of established ERMS tumors (but not ARMS tumors) formed in xenograft settings. Our findings argue that SPRY1 inhibition can offer a therapeutic strategy to treat childhood RMS and possibly other tumors carrying oncogenic RAS mutations. Cancer Res; 70(2); 762–71
Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia
Authors: Li-Zhen He, Thomas Tolentino, Peter Grayson, Sue Zhong, Raymond P. Warrell, Richard A. Rifkind, Paul A. Marks, Victoria M. Richon, Pier Paolo Pandolfi
Journal: Journal of Clinical Investigation (2001)

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations, invariably involving the retinoic acid receptor α (RARα) gene fused to one of several distinct loci, including the PML or PLZF genes, involved in t(15;17) or t(11;17), respectively. Patients with t(15;17) APL respond well to retinoic acid (RA) and other treatments, whereas those with t(11;17) APL do not. The PML-RARα and PLZF-RARα fusion oncoproteins function as aberrant transcriptional repressors, in part by recruiting nuclear receptor-transcriptional corepressors and histone deacetylases (HDACs). Transgenic mice harboring the RARα fusion genes develop forms of leukemia that faithfully recapitulate both the clinical features and the response to RA observed in humans with the corresponding translocations. Here, we investigated the effects of HDAC inhibitors (HDACIs) in vitro and in these animal models. In cells from PLZF-RARα/RARα-PLZF transgenic mice and cells harboring t(15;17), HDACIs induced apoptosis and dramatic growth inhibition, effects that could be potentiated by RA. HDACIs also increased RA-induced differentiation. HDACIs, but not RA, induced accumulation of acetylated histones. Using microarray analysis, we identified genes induced by RA, HDACIs, or both together. In combination with RA, all HDACIs tested overcame the transcriptional repression exerted by the RARα fusion oncoproteins. In vivo, HDACIs induced accumulation of acetylated histones in target organs. Strikingly, this combination of agents induced leukemia remission and prolonged survival, without apparent toxic side effects.
Neuropharmacology of the Naturally Occurring κ-Opioid Hallucinogen Salvinorin A
Authors: Christopher W. Cunningham, Richard B. Rothman, Thomas E. Prisinzano
Journal: Pharmacological Reviews (2011)

<i>Salvia divinorum</i> is a perennial sage native to Oaxaca, Mexico, that has been used traditionally in divination rituals and as a treatment for the "semimagical" disease <i>panzón de borrego</i>. Because of the intense "out-of-body" experiences reported after inhalation of the pyrolized smoke, <i>S. divinorum</i> has been gaining popularity as a recreational hallucinogen, and the United States and several other countries have regulated its use. Early studies isolated the neoclerodane diterpene salvinorin A as the principal psychoactive constituent responsible for these hallucinogenic effects. Since the finding that salvinorin A exerts its potent psychotropic actions through the activation of KOP receptors, there has been much interest in elucidating the underlying mechanisms behind its effects. These effects are particularly remarkable, because 1) salvinorin A is the first reported non-nitrogenous opioid receptor agonist, and 2) its effects are not mediated by the 5-HT<sub>2A</sub> receptor, the classic target of hallucinogens such as lysergic acid diethylamide and mescaline. Rigorous investigation into the structural features of salvinorin A responsible for opioid receptor affinity and selectivity has produced numerous receptor probes, affinity labels, and tools for evaluating the biological processes responsible for its observed psychological effects. Salvinorin A has therapeutic potential as a treatment for pain, mood and personality disorders, substance abuse, and gastrointestinal disturbances, and suggests that nonalkaloids are potential scaffolds for drug development for aminergic G-protein coupled receptors.
Combination of Factor H Mutation and Properdin Deficiency Causes Severe C3 Glomerulonephritis
Authors: Allison M. Lesher, Lin Zhou, Yuko Kimura, Sayaka Sato, Damodar Gullipalli, Andrew P. Herbert, Paul N. Barlow, Hannes U. Eberhardt, Christina Skerka, Peter F. Zipfel, Takayuki Hamano, Takashi Miwa, Kenneth S. Tung, Wen-Chao Song
Journal: Journal of the American Society of Nephrology (2012)

Factor H (fH) and properdin both modulate complement; however, fH inhibits activation, and properdin promotes activation of the alternative pathway of complement. Mutations in fH associate with several human kidney diseases, but whether inhibiting properdin would be beneficial in these diseases is unknown. Here, we found that either genetic or pharmacological blockade of properdin, which we expected to be therapeutic, converted the mild C3 GN of an fH-mutant mouse to a lethal C3 GN with features of human dense deposit disease. We attributed this phenotypic change to a differential effect of properdin on the dynamics of alternative pathway complement activation in the fluid phase and the cell surface in the fH-mutant mice. Thus, in fH mutation-related C3 glomerulopathy, additional factors that impact the activation of the alternative pathway of complement critically determine the nature and severity of kidney pathology. These results show that therapeutic manipulation of the complement system requires rigorous disease-specific target validation.
Acupuncture anesthesia. Western medicine and Chinese traditional medicine
Authors: E. G. Dimond
Journal: JAMA (1971)

In September 1971, Paul Dudley White, myself, and our wives were invited to the People's Republic of China by the China Medical Association. We were asked by our Chinese hosts to indicate specific interests, and among these I identified acupuncture. In a previous report in the<i>New England Journal of Medicine</i><sup>1</sup>I described my acupuncture experience in Saigon. Earlier (1946-1947) I had seen the practice of acupuncture and moxa in Japan. The China Medical Association and the many individual physicians could not have been kinder, and made every effort to allow me to see the full range of medical practice in China today. The practice of medicine and the national policy of China are inseparable and this report can only be rational if the political reality is identified.
Spatial Patterns and Socioecological Drivers of Dengue Fever Transmission in Queensland, Australia
Authors: Wenbiao Hu, Archie Clements, Gail Williams, Shilu Tong, Kerrie Mengersen
Journal: Environmental Health Perspectives (2011)

Understanding how socioecological factors affect the transmission of dengue fever (DF) may help to develop an early warning system of DF.We examined the impact of socioecological factors on the transmission of DF and assessed potential predictors of locally acquired and overseas-acquired cases of DF in Queensland, Australia.We obtained data from Queensland Health on the numbers of notified DF cases by local government area (LGA) in Queensland for the period 1 January 2002 through 31 December 2005. Data on weather and the socioeconomic index were obtained from the Australian Bureau of Meteorology and the Australian Bureau of Statistics, respectively. A Bayesian spatial conditional autoregressive model was fitted at the LGA level to quantify the relationship between DF and socioecological factors.Our estimates suggest an increase in locally acquired DF of 6% [95% credible interval (CI): 2%, 11%] and 61% (95% CI: 2%, 241%) in association with a 1-mm increase in average monthly rainfall and a 1°C increase in average monthly maximum temperature between 2002 and 2005, respectively. By contrast, overseas-acquired DF cases increased by 1% (95% CI: 0%, 3%) and by 1% (95% CI: 0%, 2%) in association with a 1-mm increase in average monthly rainfall and a 1-unit increase in average socioeconomic index, respectively.Socioecological factors appear to influence the transmission of DF in Queensland, but the drivers of locally acquired and overseas-acquired DF may differ. DF risk is spatially clustered with different patterns for locally acquired and overseas-acquired cases.
False-Positive Test Results in a Patient With Severe Hepatitis
Authors: Simina R. Luca, Mandana Kayedi, Brian M. Wong
Journal: JAMA Internal Medicine (2014)

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