tbuckley/cabot-search huggingface dataset:
Applying Sensitivity Analyses to Overall Survival in Cancer Clinical Trials
Authors: Steven N. Wolff
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: “Role of Sensitivity Analyses in Assessing Progression-Free Survival in Late-Stage Oncology Trials” by Bhattacharya et al is an important statistical technique that assesses whether the results of phase III trials are robust and likely to be generalizable. The authors focus their comments and state that it is “important to conduct additional analyses (sensitivity analyses) of studies where progression-free survival (PFS) or time to tumor progression (TTP) is the primary end point.” Thus, implied in their emphasis is that overall survival (OS), the ultimate gold-standard outcome (the time from random assignment to death), may not be subject to confounding issues and does not require similar consideration. Bhattacharya et al state that “the documented date of first progression is often after the actual true (unknown) date of progression, which is not the case for OS.” However, they do not consider events that could similarly affect the timing of the OS primary event. Death, although an objective and measurable event, is affected by various clinical acts that can substantially influence this outcome. It is not the issue of when death occurred but various influences that affect the outcome. For instance, similar patients failing interventional therapy at the same time point after therapy may be kept alive (eg, avoiding the primary outcome) by heroic measures such as intensive care unit care or simple measures such as treating a pneumonia, or some may have only basic noninterventional hospice/end-of-life therapy offered that does not artificially prolong survival. Additionally, patients with bulky tumors compared with those with trivial tumor burdens, similarly failing therapy at the same time point without further therapy, may have different survival outcomes unrelated to the primary interventional therapy. It is therefore equally important for sensitivity testing to be pursued when phase III studies are positive for OS when differences are statistically different, but not robust biologically, because it is becoming more common for outcomes to be measured in a few weeks or months when large numbers of patients are entered on a trial. This is especially important when drugs or biologic are approved for generalizable intervention based on modest time increments for OS.
Origin of femoro-popliteal occlusions.
Authors: J. K. Watt
Journal: BMJ (1965)

In 1950 Lindbom published the results of a radiological survey of atherosclerotic lesions in 356 legs of 185 cadavers and in 295 arteriograms of 205 patients with arterial insufficiency.He identified two principal sites of origin for femoro-popliteal occlusions, the main one being in the adductor region and the subsidiary in the popliteal artery above the level of the knee-joint.In this survey a similar though simpler and more graphic method has been used to analyse the bilateral femoral arteriograms of a comprehensive group of 264 male patients suffering from intermittent claudication.The information obtained suggests that there are three principal sites of origin of femoro- popliteal occlusions, and the relative incidence of occlusion at these sites has been assessed. MaterialFemoral arteriography, unlike aortography, is a simple and safe procedure and has been employed routinely in the Unit in all suitable patients, except the very old and unfit.The arterial tree from the groin to lower calf or ankle is readily visualized with 60% Urografin on unscreened films placed in a 3-tray cassette tunnel operated manually.From the middle of 1957, when the Unit opened, to the end of 1960 over 300 male patients with intermittent claudica- tion due to femoro-popliteal or tibial lesions were examined, and the majority were investigated by bilateral femoral arterio- graphy.When the arteriograms of those whose claudication appeared to be due to cardiac insufficiency (six cases) or anaemia (one case) were excluded, together with arteriograms technically unsatisfactory in either leg, there remained 528 arteriograms in 264 patients-approximately 85% of the original number seen in the out-patient department.
Randomized Dose-Ranging Trial of Tamoxifen at Low Doses in Hormone Replacement Therapy Users
Authors: Andrea Decensi, Sara Gandini, Davide Serrano, Massimiliano Cazzaniga, Maria Pizzamiglio, Fausto Maffini, Giuseppe Pelosi, Cristina Daldoss, Umberto Omodei, Harriet Johansson, Debora Macis, Matteo Lazzeroni, Mauro Penotti, Laura Sironi, Simona Moroni, Vanda Bianco, Gabriella Rondanina, Jennifer Gjerde, Aliana Guerrieri-Gonzaga, Bernardo Bonanni
Journal: Journal of Clinical Oncology (2007)

The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms.Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months.Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen.Doses of tamoxifen < or = 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.
P86 Exploring the emotional journey patients with asthma experience and the difference between childhood and adult diagnosis
Authors: Y Ochiai, NF Mathieson, C Goode, A Mulgirigama
Journal: Thorax (2013)

<h3>Background</h3> Asthma affects 5.4 million people in the UK. We wanted to explore the emotional journey patients with asthma experience during their management. <h3>Methods</h3> Market research was conducted with an independent agency to investigate the emotional journey patients with asthma experience. Methodologies used to collect this data included patient immersion interviews with ethnographic elements, video diary and the Soulmate™ Duo interview technique. Soulmate<sup>TM</sup> is a technique where for a proportion of the interview, patients interview each other without a moderator, allowing deeper insight into their experiences to be obtained. A total of 21 patients were interviewed, including partners and families to fully understand the impact of asthma on the individual affected. <h3>Results</h3> Experience of asthma varies considerably depending on whether symptoms first presented in early childhood or later in life. Patients diagnosed in childhood or infancy were found to normalise their symptoms more and may underestimate the severity of their condition, leading to lower adherence. Those diagnosed in adulthood were found to be more aware of the impact asthma was having upon their life. These patients tend to be regimented about taking medication and develop strategies to help them remember. Patients experience a range of emotional ups and downs throughout the treatment journey. The emotional dynamic was found to change with certain events, from diagnosis to their first asthma exacerbation. The key emotional themes identified with regards to asthma as a disease were feeling; 1) vulnerable and insecure of experiencing an asthma attack at any time, 2) restricted and constrained in terms of what they could do with their life, 3) tired and deflated over a battle that can never be won, 4) calm and relaxed when they did not experience symptoms. Impact on partners of patients with asthma was significant and often unrecognised. <h3>Conclusions</h3> Patients diagnosed with asthma in childhood are at risk of under-estimating their symptoms and are potentially at greater risk of being mis-managed. These patients need a deeper exploration of their asthma symptoms to optimise their management.
Spontaneous Ulnar Nerve Paresis
Authors: J. A. Carr
Journal: BMJ (1957)

BDIUTISRNAL 1415 and colon of each animal were prepared for histological examination.In no case was there seen any macroscopical or microscopical evidence of inflammatory change in the gut.A similar experiment was next carried out, but five of the mice each received 180 mg. of senna preparation daily and the other five were' given 360 mg. each day.Treat- ment was continued daily for four weeks in all, but the diet otherwise was not controlled.At the end of the experimental period all the mice were sacrificed and exam- inations made as previously.Again, no evidence whatever was obtained of anatomical " irritation," structural damage, or inflammatory reaction, despite the mild purging that was observed while the animals were under treatment.There is a prima facie case, therefore, for believing that senna at least, and probably other " irritant " purgatives as well, act not so much by direct damage to the mucosa as functionally upon some mechanism of the gut.Pharmaco- logical experiments to elucidate this are in progress.The findings so far are suggestive, but remain to be repeated and confirmed.
Intestinal mucus-derived nanoparticle-mediated activation of Wnt/β-catenin signaling plays a role in induction of liver natural killer T cell anergy in mice
Authors: Zhong-Bin Deng, Xiaoying Zhuang, Songwen Ju, Xiaoyu Xiang, Jingyao Mu, Qilong Wang, Hong Jiang, Lifeng Zhang, Mitchell Kronenberg, Jun Yan, Donald Miller, Huang-Ge Zhang
Journal: Hepatology (2012)

The Wnt/β-catenin pathway has been known to play a role in induction of immune tolerance, but its role in the induction and maintenance of natural killer T (NKT) cell anergy is unknown. We found that activation of the Wnt pathways in the liver microenvironment is important for induction of NKT cell anergy. We identified a number of stimuli triggering Wnt/β-catenin pathway activation, including exogenous NKT cell activator, glycolipid α-GalCer, and endogenous prostaglandin E2 (PGE2). Glycolipid α-GalCer treatment of mice induced the expression of wnt3a and wnt5a in the liver and subsequently resulted in a liver microenvironment that induced NKT cell anergy to α-GalCer restimulation. We also found that circulating PGE2 carried by nanoparticles is stable, and that these nanoparticles are A33+. A33+ is a marker of intestinal epithelial cells, which suggests that the nanoparticles are derived from the intestine. Mice treated with PGE2 associated with intestinal mucus-derived exosome-like nanoparticles (IDENs) induced NKT cell anergy. PGE2 treatment leads to activation of the Wnt/β-catenin pathway by inactivation of glycogen synthase kinase 3β of NKT cells. IDEN-associated PGE2 also induces NKT cell anergy through modification of the ability of dendritic cells to induce interleukin-12 and interferon-β in the context of both glycolipid presentation and Toll-like receptor–mediated pathways. Conclusion: These findings demonstrate that IDEN-associated PGE2 serves as an endogenous immune modulator between the liver and intestines and maintains liver NKT cell homeostasis. This finding has implications for development of NKT cell–based immunotherapies. (Hepatology 2013)
Respiratory Health Effects of Airborne Particulate Matter: The Role of Particle Size, Composition, and Oxidative Potential—The RAPTES Project
Authors: Maciej Strak, Nicole A.H Janssen, Krystal J Godri, Ilse Gosens, Ian S Mudway, Flemming R Cassee, Erik Lebret, Frank J Kelly, Roy M Harrison, Bert Brunekreef, Maaike Steenhof, Gerard Hoek
Journal: Environmental Health Perspectives (2012)

Specific characteristics of particulate matter (PM) responsible for associations with respiratory health observed in epidemiological studies are not well established. High correlations among, and differential measurement errors of, individual components contribute to this uncertainty.We investigated which characteristics of PM have the most consistent associations with acute changes in respiratory function in healthy volunteers.We used a semiexperimental design to accurately assess exposure. We increased exposure contrast and reduced correlations among PM characteristics by exposing volunteers at five different locations: an underground train station, two traffic sites, a farm, and an urban background site. Each of the 31 participants was exposed for 5 hr while exercising intermittently, three to seven times at different locations during March-October 2009. We measured PM10, PM2.5, particle number concentrations (PNC), absorbance, elemental/organic carbon, trace metals, secondary inorganic components, endotoxin content, gaseous pollutants, and PM oxidative potential. Lung function [FEV1 (forced expiratory volume in 1 sec), FVC (forced vital capacity), FEF25-75 (forced expiratory flow at 25-75% of vital capacity), and PEF (peak expiratory flow)] and fractional exhaled nitric oxide (FENO) were measured before and at three time points after exposure. Data were analyzed with mixed linear regression.An interquartile increase in PNC (33,000 particles/cm3) was associated with an 11% [95% confidence interval (CI): 5, 17%] and 12% (95% CI: 6, 17%) FENO increase over baseline immediately and at 2 hr postexposure, respectively. A 7% (95% CI: 0.5, 14%) increase persisted until the following morning. These associations were robust and insensitive to adjustment for other pollutants. Similarly consistent associations were seen between FVC and FEV1 with PNC, NO2 (nitrogen dioxide), and NOx (nitrogen oxides).Changes in PNC, NO2, and NOx were associated with evidence of acute airway inflammation (i.e., FENO) and impaired lung function. PM mass concentration and PM10 oxidative potential were not predictive of the observed acute responses.
AIDS-Related Cancer and Severity of Immunosuppression in Persons With AIDS
Authors: R. J. Biggar, A. K. Chaturvedi, J. J. Goedert, E. A. Engels
Journal: JNCI Journal of the National Cancer Institute (2007)

BackgroundThe incidence of Kaposi sarcoma, non-Hodgkin lymphoma, and cervical cancer has been declining among persons with AIDS. We investigated the association between cancer risk and CD4 cell count among such persons.
Congenital Heart Defects in Europe
Authors: Helen Dolk, Maria Loane, Ester Garne
Journal: Circulation (2011)

Background— This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. Methods and Results— Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of which 8.1% were perinatal deaths, 40% were prenatally diagnosed, and 14% were TOPFA (TOPFA range between countries 0% to 32%). Live-born CHD associated with Down syndrome occurred in 0.5 per 1000 births, with &gt;4-fold variation between countries. Conclusion— Annually in the European Union, we estimate 36 000 children are live born with CHD and 3000 who are diagnosed with CHD die as a TOFPA, late fetal death, or early neonatal death. Investing in primary prevention and pathogenetic research is essential to reduce this burden, as well as continuing to improve cardiac services from in utero to adulthood.
Impairment of left ventricular function by acute cardiac lymphatic obstruction
Authors: L.L Ludwig, E.R Schertel, J.W Pratt, D.E McClure, A.J Ying, C.F Heck, P.D Myerowitz
Journal: Cardiovascular Research (1997)

We performed the following study to define the effects of acute cardiac lymphatic obstruction on left ventricular (LV) systolic and diastolic function.Cardiac lymphatic obstruction was created in 8 pentobarbital-anesthetized dogs by identifying (Evans blue) and ligating the right and left epicardial lymphatics, the afferent and efferent lymphatics associated with the pretrachael and cardiac lymph nodes, and the thoracic duct. Left ventricular function was assessed by analysis of micromanometer-conductance catheter-derived LV pressure-volume relationships. Contractility was assessed by preload recruitable stroke work (PRSW). The active and passive phases of LV relaxation were assessed by the time constant o isovolumic relaxation (tau) and the end-diastolic pressure-volume relationship (stiffness), respectively.PRSW decreased significantly and tau increased significantly from baseline at 1, 2, and 3 h after cardiac lymphatic obstruction (n = 8), but stiffness did not change. Cardiac lymphatic obstruction had similar effects on LV function in a group of autonomically blocked dogs (n = 5). Left ventricular function did not change in sham treated controls (n = 8). Cardiac lymphatic obstruction induced a significant increase in LV wet/dry weight ratios (3.58 +/- 0.01) when compared to the control group (3.53 +/- 0.02). Histopathology of the myocardium in the lymphatic obstruction groups revealed significant lymphangiectasis and increased interstitial spacing when compared to controls.Acute cardiac lymphatic obstruction depresses contractility and active relaxation and causes mild LV myocardial edema, but does not alter diastolic stiffness.
Cardiac Angiotensin II Participates in Coronary Microvessel Inflammation of Unstable Angina and Strengthens the Immunomediated Component
Authors: Gian Gastone Neri Serneri, Maria Boddi, Pietro Amedeo Modesti, Mirella Coppo, Ilaria Cecioni, Thomas Toscano, Maria Letizia Papa, Manuela Bandinelli, Gian Franco Lisi, Mario Chiavarelli
Journal: Circulation Research (2004)

Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (n=43) and stable angina (SA) (n=15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (P<0.01). UA biopsy samples showed numerous DR+ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-alpha, IL-6, IFN-gamma, and iNOS genes (P<0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-alpha, IL-6, and iNOS, and, to a lesser extent, of IFN-gamma genes, but did not affect the number of DR+ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina.
Mental disorders in prison populations aged 15-21: national register study of two cohorts in Finland
Authors: Eila S Sailas, Benjamin Feodoroff, Matti Virkkunen, Kristian Wahlbeck
Journal: BMJ (2005)

Juvenile delinquency is linked to psychiatric morbidity. 1w1-w9 We were interested in temporal changes in psychiatric morbidity in offenders.Criminal policy in many Western countries emphasises the need for alternative methods of punishment for adolescent prisoners. 2In Finland, successful policy to diminish the number of adolescents in prisons has been internationally recognised. 3We studied the changes in psychiatric hospitalisations in Finnish prisoners aged 15 to 21 to see whether a selection process occurs as the number of young prisoners decreases. What this study addsMore mentally ill young people end up in prison as the prison population diminishes
How reliably do rheumatologists measure shoulder movement?
Authors: J L Hoving
Journal: Annals of the Rheumatic Diseases (2002)

<b>Objective:</b> To assess the intrarater and interrater reliability among rheumatologists of a standardised protocol for measurement of shoulder movements using a gravity inclinometer. <b>Methods:</b> After instruction, six rheumatologists independently assessed eight movements of the shoulder, including total and glenohumeral flexion, total and glenohumeral abduction, external rotation in neutral and in abduction, internal rotation in abduction and hand behind back, in random order in six patients with shoulder pain and stiffness according to a 6×6 Latin square design using a standardised protocol. These assessments were then repeated. Analysis of variance was used to partition total variability into components of variance in order to calculate intraclass correlation coefficients (ICCs). <b>Results:</b> The intrarater and interrater reliability of different shoulder movements varied widely. The movement of hand behind back and total shoulder flexion yielded the highest ICC scores for both intrarater reliability (0.91 and 0.83, respectively) and interrater reliability (0.80 and 0.72, respectively). Low ICC scores were found for the movements of glenohumeral abduction, external rotation in abduction, and internal rotation in abduction (intrarater ICCs 0.35, 0.43, and 0.32, respectively), and external rotation in neutral, external rotation in abduction, and internal rotation in abduction (interrater ICCs 0.29, 0.11, and 0.06, respectively). <b>Conclusions:</b> The measurement of shoulder movements using a standardised protocol by rheumatologists produced variable intrarater and interrater reliability. Reasonable reliability was obtained only for the movement of hand behind back and total shoulder flexion.