tbuckley/cabot-search huggingface dataset:
Shifting Patterns in the Interpretation of Phase III Clinical Trial Outcomes in Advanced Non–Small-Cell Lung Cancer: The Bar Is Dropping
Authors: Adrian G. Sacher, Lisa W. Le, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2014)

Purpose Despite multiple trials of new agents in advanced non–small-cell lung cancer (NSCLC), outcomes remain poor. This study explores how the design and interpretation of randomized trials in advanced NSCLC has changed over time. Methods Phase III randomized controlled trials of systemic therapy for advanced NSCLC between 1980 and 2010 were identified, and their primary end point, outcome, statistical significance, and conclusions were recorded. Results Of 245 trials identified, 203 were eligible for study inclusion. Although overall survival remains the most common primary end point of phase III trials, more trials from the last decade have used progression-free survival instead (none in 1980 to 1990, 13% in 2001 to 2010; P = .002). The percentage of trials meeting their primary statistical end points remained stable over time; however, the percentage of trials reporting a positive outcome without meeting that end point increased (30% in 1980 to 1990, 53% in 2001 to 2010; P &lt; .001). A trend toward decreasing magnitude of survival gain in positive trials was seen over time (3.9 months in 1980 to 1990, 2.5 months in 2001 to 2010; P = .11), with a concomitant increase in the sample size of clinical trials over the same time period (median: 152 patients in 1980 to 1990, 413 in 2001 to 2010; P &lt; .001). Only studies predating 1990 reported negative results as a result of insufficient magnitude of survival benefit despite statistical significance. Conclusion A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced NSCLC. The use of survival as the primary measure of benefit is declining, as is the magnitude of benefit deemed clinically relevant.
A Systematic Review of Drug Therapy to Delay or Prevent Type 2 Diabetes
Authors: Raj Padwal, Sumit R. Majumdar, Jeff A. Johnson, Janice Varney, Finlay A. McAlister
Journal: Diabetes Care (2005)

OBJECTIVE—To systematically review the evidence for the prevention of type 2 diabetes by pharmacological therapies. RESEARCH DESIGN AND METHODS—Randomized controlled trials and cohort studies examining the effect of oral hypoglycemic agents, antiobesity agents, antihypertensive agents, statins, fibrates, and estrogen on the incidence of type 2 diabetes were identified from MEDLINE, EMBASE, the Cochrane Controlled Trials Registry, and searches of reference lists. Two reviewers independently assessed studies for inclusion and performed data extraction. RESULTS—Ten studies of oral hypoglycemic agents and 15 studies of nonoral hypoglycemic agents were found. Oral hypoglycemic agents and orlistat are the only drugs that have been studied in randomized controlled trials with diabetes incidence as the primary end point. In the largest studies of 2.5–4.0 years’ duration, metformin (relative risk [RR] 0.69, 95% CI 0.57–0.83), acarbose (0.75, 0.63–0.90), troglitazone (0.45, 0.25–0.83), and orlistat (hazard ratio [HR] 0.63, 95% CI 0.46–0.86) have all been shown to decrease diabetes incidence compared with placebo; however, follow-up rates varied from 43 to 96%. Current evidence for statins, fibrates, antihypertensive agents, and estrogen is inconclusive. In addition, the critical question of whether drugs are preventing, or simply delaying, onset of diabetes remains unresolved. CONCLUSIONS—Currently, no single agent can be definitively recommended for diabetes prevention. Future studies should be designed with diabetes incidence as the primary outcome and should be of sufficient duration to differentiate between genuine diabetes prevention as opposed to simple delay or masking of this condition.
Erythema multiforme-like lesions in syphilis
Authors: J.-Y. Lee, E.-S. Lee
Journal: British Journal of Dermatology (2003)

Sir, The clinical features and histological patterns of secondary syphilis are very variable, and commonly mimic those of other diseases.1–3 We report erythema multiforme (EM)‐like lesions in syphilis that manifested as targetoid lesions on the forearms, palms and soles. A 37‐year‐old‐woman presented with a 5‐month history of pruritic cutaneous lesions involving the forearms, palms and soles. About 4 months previously a genital ulcer had developed, which resolved spontaneously, and recurrent oral ulcers had developed over the previous 2 months. She had no prior history of medication before the skin lesions occurred. Examination revealed targetoid lesions, which were violaceous, erythematous plaques in an annular pattern, 1–1·5 cm in size, on both forearms, palms and soles (Figs 1A,B). All other physical findings were normal. The clinical findings suggested EM or secondary syphilis. Serological tests for syphilis showed venereal disease research laboratory (VDRL) test titres of 1 : 64, and the fluorescent treponemal antibody absorption test and Treponema pallidum haemagglutination assay were reactive. Skin biopsy was performed on the forearm and palm. The forearm biopsy was consistent with interface dermatitis, and showed hyperkeratosis, lymphocytic exocytosis, and vacuolization of the basal layer. A mild perivascular lymphohistiocytic infiltrate without plasma cells was present throughout the papillary dermis (Fig. 2A). The palm biopsy showed a subacute eczematous dermatitis with hyperkeratosis, minimal spongiosis and exocytosis (Fig. 2B). Swelling and proliferation of endothelial cells and a perivascular dermal infiltrate containing numerous plasma cells, which are fundamental histological findings of syphilis,4 were not seen. However, immunoperoxidase stain with avidin–biotin peroxidase complex5 demonstrated many T. pallidum in the epidermis and around the dermal blood vessels (Fig. 2C). The avidin–biotin peroxidase complex stain was done with the use of a rabbit anti‐T. pallidum serum as primary antibody (prepared in the Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea). The patient was diagnosed as having secondary syphilis and was treated with benzathine penicillin G (2·4 million units) by intramuscular injection once weekly for three consecutive weeks. One month after initiation of therapy, her skin lesions resolved leaving postinflammatory hyperpigmentation. The VDRL test titre decreased to 1 : 2 and there were no skin lesions after 7 months (Fig. 1C).
Letrozole Suppresses Plasma Estradiol and Estrone Sulphate More Completely Than Anastrozole in Postmenopausal Women With Breast Cancer
Authors: J. Michael Dixon, Lorna Renshaw, Oliver Young, Juliette Murray, E. Jane Macaskill, Mary McHugh, Elizabeth Folkerd, David A. Cameron, Roger P. A'Hern, Mitch Dowsett
Journal: Journal of Clinical Oncology (2008)

To compare the effects of anastrozole and letrozole on plasma estradiol (E2) and estrone sulfate (E1S) levels.Fifty-four postmenopausal women with estrogen receptor-positive breast cancer receiving aromatase inhibitors (AIs) as part of their adjuvant therapy were randomly assigned to receive either 3 months of anastrozole (1 mg) followed by 3 months of letrozole (2.5 mg), both given orally once daily, or 3 months of the opposite sequence. Blood was taken at the same time and the same day of the week from each patient, before and after 3 months of each drug, and plasma levels of E2 and E1S were determined using highly sensitive radioimmunoassays.There were 27 patients in each group. The mean age of the patients was 63 years (range, 49 to 83 years). Baseline E2 levels ranged from 3 pmol/L to 91 pmol/L with a mean of 25.7 pmol/L. Only one of 54 (2%) patients had an E2 value >or= 3 pmol/L after receiving letrozole, versus 20 of 54 (37%) patients after receiving anastrozole (P < .001). Extrapolation revealed a mean E2 level after anastrozole treatment of 2.71 pmol/L (range, 2.38 to 3.08 pmol/L). Following letrozole, it was 1.56 pmol/L (range, 1.37 to 1.78 pmol/L). Mean residual E2 was 10.1% for anastrozole and 5.9% for letrozole. Residual E1S levels were 4.6% for anastrozole and 2.0% for letrozole (P = .001).Letrozole reduces plasma E2 and E1S levels to a significantly greater extent than anastrozole in postmenopausal women taking AIs as part of their adjuvant therapy for hormone receptor-positive breast cancer.
Non-steroidal anti-inflammatory drugs: overall risks and management. Complementary roles for COX-2 inhibitors and proton pump inhibitors
Authors: C J Hawkey
Journal: Gut (2003)

Non-steroidal anti-inflammatory drugs (NSAIDs) are well recognised as causing peptic ulceration and ulcer complications. However, several critical issues, including the amount of both gastrointestinal and non-gastrointestinal disease affected by NSAIDs, their interaction with ancillary risk factors, and how to optimise management in subgroups, remain poorly understood. In this article, strategies for subgroups that take account of non-specific gastrointestinal risks, minimisation of residual risk, and the importance of non-gastrointestinal toxicity are suggested, and areas for research identified.
Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial
Authors: Patricia Jabre, Xavier Combes, Frederic Lapostolle, Mohamed Dhaouadi, Agnes Ricard-Hibon, Benoit Vivien, Lionel Bertrand, Alexandra Beltramini, Pascale Gamand, Stephane Albizzati, Deborah Perdrizet, Gaelle Lebail, Charlotte Chollet-Xemard, Virginie Maxime, Christian Brun-Buisson, Jean-Yves Lefrant, Pierre-Edouard Bollaert, Bruno Megarbane, Jean-Damien Ricard, Nadia Anguel, Eric Vicaut, Frederic Adnet
Journal: The Lancet (2009)
What is “quality of evidence” and why is it important to clinicians?
Authors: Gordon H Guyatt, Andrew D Oxman, Regina Kunz, Gunn E Vist, Yngve Falck-Ytter, Holger J Schünemann
Journal: BMJ (2008)

Guideline developers use a bewildering variety of systems to rate the quality of the evidence underlying their recommendations. Some are facile, some confused, and others sophisticated but complex
Translocation of p21Cip1/WAF1 from the nucleus to the cytoplasm correlates with pancreatic myofibroblast to fibroblast cell conversion
Authors: F Manapov
Journal: Gut (2005)

<b>Background and aims:</b> In the pancreas, myofibroblasts (MFBs) were shown to play an important role in the cellular response during inflammation and injury. However, there is only fragmentary information concerning the fate of these cells in pancreas regeneration and fibrosis development. <b>Methods:</b> Explant cultures of rat pancreatic tissue were used as a model to follow cellular dynamics and phenotype conversion of pancreatic MFBs in vitro. For detailed biochemical analyses a pancreatic fibroblast cell line (long culture fibroblast (LCF)) was generated from MFBs in a long term culture. Cerulein induced acute pancreatitis and dibutyltin dichloride induced pancreas fibrosis were used as experimental models for acute and chronic fibrogenic reactions, respectively. <b>Results:</b> In the explant culture, pancreatic MFBs which derived from fat storing fibroblastic cells underwent apoptosis or converted again to fibroblasts. The phenotype switch to fibroblasts was associated with translocation of p21<sup>Cip1/WAF1</sup> from the nucleus into the cytoplasm. Molecular analyses in LCFs revealed subsequent binding to and inhibition of the activities of Rho kinase 2 and apoptosis signal regulating kinase 1. In the experimentally established pancreas fibrosis, fibroblasts with cytoplasmic expression of p21<sup>Cip1/WAF1</sup> were distributed throughout fibrotic bands whereas in experimental acute pancreatitis MFBs with nuclear expression of p21<sup>Cip1/WAF1</sup> dominated. <b>Conclusions:</b> The results indicate that pancreatic MFBs are transient and suggest that intracellular localisation of p21<sup>Cip1/WAF1</sup> can contribute to the phenotype conversion of these cells to fibroblasts in culture and experimental injury.
Diabetes, Exercise, and Atherosclerosis
Authors: Neil B Ruderman, Stephen H Schneider
Journal: Diabetes Care (1992)

Regular exercise may diminish the risk for atherosclerotic vascular disease in patients with non-insulin-dependent (type II) diabetes and in the general population. The basis for this effect of exercise may be its ability to diminish or prevent hyperinsulinemia, insulin resistance, and/or increases in intra-abdominal adipose mass. These abnormalities are associated with premature atherosclerotic vascular disease, essential hypertension, type II diabetes, and certain dyslipoproteinemias, and most likely precede them. They also have been implicated in the pathogenesis of these disorders. We propose that the high prevalence of hyperinsulinemia and insulin resistance in individuals leading a western life-style accounts for the reported benefit of physical activity in preventing coronary heart disease in the general population. We also propose that exercise (and diet) are most likely to be effective when initiated in young individuals, before the onset of irreversible vascular alterations, and when life-style changes may be more acceptable. Early identification of such individuals may be possible on the basis of family history, the presence of components of the hyperinsulinemia-insulin resistance syndrome, and/or central obesity. One such group that may already have been identified is women with gestational diabetes.
Assessing decision of inpatient or outpatient care in community acquired pneumonia patients: Results of APT care study
Authors: Saleem Ullah, Javaid Ahmed Khan, Amanullah Khan, Irfan Hashemy
Journal: European Respiratory Journal (2014)

Background: An important decision in managing Community Acquired Pneumonia (CAP) patients relates to their hospitalization. CURB 65 (Confusion, Urea, Respiratory rate, Blood pressure, age ≥ 65 years), a prediction tool helps in decision making. This study estimates the proportion of CAP patients with disagreement between CURB 65 recommendation and physician9s decision to hospitalize/not hospitalize.  Methods: This cross-sectional multicentre study recruited consenting adult patients with a confirmatory diagnosis of CAP on Chest X-ray. CURB 65 recommendation for each patient was determined at the time of data analysis. This recommendation was compared with treatment decision made by the physician. Disagreement (expressed as a proportion) was considered when the physician9s decision did not match with the recommendation.  Results: Between December 2011 and May 2012, 22 investigators across ten cities in Pakistan gathered information on 352 eligible patients (57.1% males, mean age: 50.7 (±18.5) years). In 40% (140/352) patients there was a disagreement between CURB-65 recommendation and physician9s decision of hospitalization or outpatient care. Of the 352 cases 37.5% (132) were hospitalized despite CURB 65 recommendation of outpatient treatment. Levofloxacin was the most commonly (15%) prescribed mono therapeutic agent whereas ceftriaxone was commonly (30%) prescribed in combination therapy.  Conclusion: In this first nation-wide study in four out of ten patients there was disagreement between CURB 65 recommendation and the physician9s decision on whether or not to hospitalize CAP patients.
NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition
Authors: S. Javadov, A. Choi, V. Rajapurohitam, A. Zeidan, A. G. Basnakian, M. Karmazyn
Journal: Cardiovascular Research (2007)

The possible contribution of the cardiac mitochondrial permeability transition pore (PTP) towards the cardioprotective effects of Na+–H+ exchanger-1 (NHE-1) inhibition was studied in hearts subjected to ischaemia/reperfusion (IR). Langendorff-perfused rat hearts were subjected to 40 min of global ischaemia and 60 min of reperfusion in the presence or absence of the NHE-1 specific inhibitor AVE-4890 (AVE, 5 µM). Mitochondrial PTP opening was determined in the intact heart using 2-deoxy-[3H]-glucose entrapment and in isolated mitochondria by monitoring the decrease of the calcium-induced light scattering. Mitochondrial respiration was measured with a Clark-type oxygen electrode whereas release of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) and levels of cleaved poly-(ADP-ribose) polymerase (PARP) were analysed by western blotting. IR induced mitochondrial PTP opening, which was inhibited by 28% (P < 0.05) with AVE treatment. Mitochondria isolated from AVE-treated hearts demonstrated significantly less calcium-induced swelling and higher substrate oxidation at complex I and II as well as cytochrome c oxidase and citrate synthase activity. AVE treatment also suppressed IR-induced release of AIF and EndoG from mitochondria, prevented the IR-induced rise in cleaved PARP levels, and was associated with significantly enhanced postischaemic recovery of left ventricular developed pressure and a significant decrease in lactate dehydrogenase release. AVE did not affect PTP opening directly in isolated mitochondria. The beneficial effect of NHE-1 inhibition in hearts subjected to IR is associated with attenuation of mitochondrial PTP opening and apoptosis and the resultant mitochondrial dysfunction. The effect of AVE on PTP opening most likely is indirect, as pore opening was not affected by direct administration of AVE to mitochondrial suspensions.
DETERMINANTS OF LYMPHOID-MYELOID LINEAGE DIVERSIFICATION
Authors: Catherine V. Laiosa, Matthias Stadtfeld, Thomas Graf
Journal: Annual Review of Immunology (2006)

In recent years, investigators have made great progress in delineating developmental pathways of several lymphoid and myeloid lineages and in identifying transcription factors that establish and maintain their fate. However, the developmental branching points between these two large cell compartments are still controversial, and little is known about how their diversification is induced. Here, we give an overview of determinants that play a role at lymphoid-myeloid junctures, in particular transcription factors and cytokine receptors. Experiments showing that myeloid lineages can be reversibly reprogrammed into one another by transcription factor network perturbations are used to highlight key principles of lineage commitment. We also discuss experiments showing that lymphoid-to-myeloid but not myeloid-to-lymphoid conversions can be induced by the enforced expression of a single transcription factor. We close by proposing that this asymmetry is related to a higher complexity of transcription factor networks in lymphoid cells compared with myeloid cells, and we suggest that this feature must be considered when searching for mechanisms by which hematopoietic stem cells become committed to lymphoid lineages.
Noninvasive Ventilation Reduces Mortality in Acute Respiratory Failure following Lung Resection
Authors: IGOR AURIANT, ANNE JALLOT, PHILIPPE HERVÉ, JACQUES CERRINA, FRANCOIS LE ROY LADURIE, JEAN LAMET FOURNIER, BERNARD LESCOT, FRANCOIS PARQUIN
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

When treated with invasive endotracheal mechanical ventilation (ETMV), acute respiratory insufficiency after lung resection is fatal in up to 80% of cases. Noninvasive positive-pressure ventilation (NPPV) may reduce the need for ETMV, thereby improving survival. We conducted a randomized prospective trial to compare standard therapy with and without nasal-mask NPPV in patients with acute hypoxemic respiratory insufficiency after lung resection. The primary outcome variable was the need for ETMV and the secondary outcome variables were in-hospital and 120-d mortality rates, duration of stay in the intensive care unit, and duration of in-hospital stay. Twelve of the 24 patients (50%) randomly assigned to the no-NPPV group required ETMV, versus only five of the 24 patients (20.8%) in the NPPV group (p = 0.035). Nine patients in the no-NPPV group died (37.5%), and three (12.5 %) patients in the NPPV group died (p = 0.045). The other secondary outcomes were similar in the two groups. NPPV is safe and effective in reducing the need for ETMV and improving survival after lung resection.
Creating active environments across the life course: “thinking outside the square”
Authors: B Giles-Corti, A C King
Journal: British Journal of Sports Medicine (2009)

The built environment and physical activity agenda provides a unique opportunity for public health, physical activity and planning researchers to be front and centre of a movement aimed at creating healthier and more sustainable environments. However, in order to optimise environments that encourage physical activity across the life course, researchers in this field need to think beyond their “square” —that is, the target group, setting and physical activity behaviour with which they work. We suggest that researchers working in this field need a better understanding of systems theory to appreciate that a change to one part of a complex system can positively and negatively influence other parts of the system. An understanding of systems theory would help minimise unintended negative consequences to other population subgroups or to other types of physical activity from the implementation of our research findings. In this way, a more comprehensive set of research, practice and programme-related activities may emerge, which will advance physical activity research and practice, and improve population health across the life course.
Association of NSAID Use With Risk of Bleeding and Cardiovascular Events in Patients Receiving Antithrombotic Therapy After Myocardial Infarction
Authors: Anne-Marie Schjerning Olsen, Gunnar H. Gislason, Patricia McGettigan, Emil Fosbøl, Rikke Sørensen, Morten Lock Hansen, Lars Køber, Christian Torp-Pedersen, Morten Lamberts
Journal: JAMA (2015)

Antithrombotic treatment is indicated for use in patients after myocardial infarction (MI); however, concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) could pose safety concerns.To examine the risk of bleeding and cardiovascular events among patients with prior MI taking antithrombotic drugs and for whom NSAID therapy was then prescribed.Using nationwide administrative registries in Denmark (2002-2011), we studied patients 30 years or older admitted with first-time MI and alive 30 days after discharge. Subsequent treatment with aspirin, clopidogrel, or oral anticoagulants and their combinations, as well as ongoing concomitant NSAID use, was determined.Use of NSAIDs with ongoing antithrombotic treatment after first-time MI.Risk of bleeding (requiring hospitalization) or a composite cardiovascular outcome (cardiovascular death, nonfatal recurrent MI, and stroke) according to ongoing NSAID and antithrombotic therapy, calculated using adjusted time-dependent Cox regression models.We included 61,971 patients (mean age, 67.7 [SD, 13.6] years; 63% men); of these, 34% filled at least 1 NSAID prescription. The number of deaths during a median follow-up of 3.5 years was 18,105 (29.2%). A total of 5288 bleeding events (8.5%) and 18,568 cardiovascular events (30.0%) occurred. The crude incidence rates of bleeding (events per 100 person-years) were 4.2 (95% CI, 3.8-4.6) with concomitant NSAID treatment and 2.2 (95% CI, 2.1-2.3) without NSAID treatment, whereas the rates of cardiovascular events were 11.2 (95% CI, 10.5-11.9) and 8.3 (95% CI, 8.2-8.4). The multivariate-adjusted Cox regression analysis found increased risk of bleeding with NSAID treatment compared with no NSAID treatment (hazard ratio, 2.02 [95% CI, 1.81-2.26]), and the cardiovascular risk was also increased (hazard ratio, 1.40 [95% CI, 1.30-1.49]). An increased risk of bleeding and cardiovascular events was evident with concomitant use of NSAIDs, regardless of antithrombotic treatment, types of NSAIDs, or duration of use.Among patients receiving antithrombotic therapy after MI, the use of NSAIDs was associated with increased risk of bleeding and excess thrombotic events, even after short-term treatment. More research is needed to confirm these findings; however, physicians should exercise appropriate caution when prescribing NSAIDs for patients who have recently experienced MI.