tbuckley/cabot-search huggingface dataset:
Comparison of Sentinel Lymph Node Biopsy Alone and Completion Axillary Lymph Node Dissection for Node-Positive Breast Cancer
Authors: Karl Y. Bilimoria, David J. Bentrem, Nora M. Hansen, Kevin P. Bethke, Alfred W. Rademaker, Clifford Y. Ko, David P. Winchester, David J. Winchester
Journal: Journal of Clinical Oncology (2009)

Purpose For women with breast cancer, the role of completion axillary lymph node dissection (ALND) after identification of nodal metastases by sentinel lymph node biopsy (SLNB) has been questioned. Our objectives were to assess national nodal evaluation practice patterns and to examine differences in recurrence and survival for SLNB alone versus SLNB with completion ALND. Patients and Methods From the National Cancer Data Base (1998 to 2005), women with clinically node-negative breast cancer who underwent SLNB and who had nodal metastases were identified. Practice patterns and outcomes were examined for patients who underwent SLNB alone versus SLNB with completion ALND (median follow-up, 63 months). Results Of 97,314 patients, 20.8% underwent SLNB alone, and 79.2% underwent SLNB with completion ALND. In 2004 to 2005, patients were significantly more likely to undergo SLNB alone if they were older, had smaller tumors, or were treated at non–National Cancer Institute–designated cancer centers. In patients with macroscopic nodal metastases (n = 20,075 during 1998 to 2000), there was a nonsignificant trend toward better outcomes for completion ALND (v SLNB alone) after analysis was adjusted for differences between the two groups: axillary recurrence (hazard ratio [HR], 0.58; 95% CI, 0.32 to 1.06) and overall survival (HR, 0.89; 95% CI, 0.76 to 1.04). In patients with microscopic nodal metastases (n = 2,203 during 1998 to 2000), there were no significant differences in axillary recurrence or survival for patients who underwent SLNB alone versus completion ALND. Conclusion Compared with SLNB alone, completion ALND does not appear to improve outcomes for breast cancer patients with microscopic nodal metastases; however, there was a nonsignificant trend toward better outcomes with completion ALND for those with macroscopic disease.
Preferential regulation of duplicated genes by microRNAs in mammals
Authors: Jingjing Li, Gabriel Musso, Zhaolei Zhang
Journal: Genome biology (2008)

Although recent advances have been made in identifying and analyzing instances of microRNA-mediated gene regulation, it remains unclear by what mechanisms attenuation of transcript expression through microRNAs becomes an integral part of post-transcriptional modification, and it is even less clear to what extent this process occurs for mammalian gene duplicates (paralogs). Specifically, while mammalian paralogs are known to overcome their initial complete functional redundancy through variation in regulation and expression, the potential involvement of microRNAs in this process has not been investigated.We comprehensively investigated the impact of microRNA-mediated post-transcriptional regulation on duplicated genes in human and mouse. Using predicted targets derived from several analysis methods, we report the following observations: microRNA targets are significantly enriched for duplicate genes, implying their roles in the differential regulation of paralogs; on average, duplicate microRNA target genes have longer 3' untranslated regions than singleton targets, and are regulated by more microRNA species, suggesting a more sophisticated mode of regulation; ancient duplicates were more likely to be regulated by microRNAs and, on average, have greater expression divergence than recent duplicates; and ancient duplicate genes share fewer ancestral microRNA regulators, and recent duplicate genes share more common regulating microRNAs.Collectively, these results demonstrate that microRNAs comprise an important element in evolving the regulatory patterns of mammalian paralogs. We further present an evolutionary model in which microRNAs not only adjust imbalanced dosage effects created by gene duplication, but also help maintain long-term buffering of the phenotypic consequences of gene deletion or ablation.
Better Information for Better Health Care: The Evidence-based Practice Center Program and the Agency for Healthcare Research and Quality
Authors: David Atkins
Journal: Annals of Internal Medicine (2005)

To provide decision makers with the best available evidence, the Agency for Healthcare Research and Quality established a network of Evidence-based Practice Centers across North America. The centers perform systematic reviews on important questions posed by partner organizations about clinical, organizational, and policy interventions in health care. The Agency works closely with partners and other decision maker s to help translate that evidence into practice or policy. In this paper, we review important lessons we have learned over the past 7 years about how to increase the efficiency and impact of systematic reviews. Lessons concern selecting the right topics and scope, working effectively with partners, and balancing consistency and flexibility in methods. We examine continuing evolutions of the program and the impact of planned work on comparative effectiveness performed as part of the Medicare Modernization Act of 2003.
Effect of virtual endoscopy simulator training on performance of upper gastrointestinal endoscopy in patients: a randomized controlled trial
Authors: A. Ferlitsch, R. Schoefl, A. Puespoek, W. Miehsler, M. Schoeniger-Hekele, H. Hofer, A. Gangl, M. Homoncik
Journal: Endoscopy (2010)

Background: Skills in gastrointestinal endoscopy mainly depend on experience and practice. Patients upon whom trainees perform their first endoscopic examinations are likely to suffer more discomfort and prolonged procedures. Training on endoscopy simulators may reduce the time required to reach competency in patient endoscopy.
Clinical and Serologic Manifestations of Autoimmune Disease in MRL-<i>lpr/lpr</i> Mice Lacking Nitric Oxide Synthase Type 2
Authors: Gary S. Gilkeson, John S. Mudgett, Michael F. Seldin, Phil Ruiz, Audrey A. Alexander, Mary A. Misukonis, David S. Pisetsky, J. Brice Weinberg
Journal: The Journal of Experimental Medicine (1997)

Nitric oxide (NO) is an important mediator of the inflammatory response. MRL–lpr/lpr mice overexpress inducible nitric oxide synthase (NOS2) and overproduce NO in parallel with the development of an autoimmune syndrome with a variety of inflammatory manifestations. In previous studies, we showed that inhibiting NO production with the nonselective nitric oxide synthase (NOS) inhibitor NG-monomethyl–arginine reduced glomerulonephritis, arthritis, and vasculitis in MRL–lpr/lpr mice. To define further the role of NO and NOS2 in disease in MRL–lpr/lpr mice, mice with targeted disruption of NOS2 were produced by homologous recombination and bred to MRL–lpr/lpr mice to the N4 generation. MRL–lpr/lpr littermates homozygous for disrupted NOS2 (−/−), heterozygous for disrupted NOS2 (+/−), or wildtype (+/+) were derived for this study. Measures of NO production were markedly decreased in the MRL-lpr/lpr (−/−) mice compared with MRL-lpr/lpr (+/+) mice, with intermediate production by the MRL-lpr/lpr (+/−) mice. There was no detectable NOS2 protein by immunoblot analysis of the spleen, liver, kidney, and peritoneal macrophages of the (−/−) animals, whereas that of (+/+) was high and (+/−) intermediate. The (−/−) mice developed glomerular and synovial pathology similar to that of the (+/−) and (+/+) mice. However, (−/−) mice and (+/−) mice had significantly less vasculitis of medium-sized renal vessels than (+/+) mice. IgG rheumatoid factor levels were significantly lower in the (−/−) mice as compared with (+/+) mice, but levels of anti-DNA antibodies were comparable in all groups. Our findings show that NO derived from NOS2 has a variable impact on disease manifestations in MRL-lpr/lpr mice, suggesting heterogeneity in disease mechanisms.
The shape of things to come: mitochondrial fusion and fission in the adult heart
Authors: A. R. Hall, D. J. Hausenloy
Journal: Cardiovascular Research (2012)

This editorial refers to ‘Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload’, by J. Piquereau et al ., pp. 408–417, this issue. 

Mitochondrial research is undergoing something of a renaissance with the discovery that mitochondria are no longer considered to be static, rod-shaped organelles whose only role within the cell is to generate ATP. In fact, mitochondria are highly mobile organelles, capable of changing their shape by undergoing ‘fusion’ (to form elongated, interconnected mitochondria) and ‘fission’ (to form fragmented, discrete mitochondria).1,2 Changes in mitochondrial morphology are regulated by the evolutionarily conserved mitochondrial fusion proteins, mitofusins 1 and 2 (Mfn1 and Mfn2) and optic atrophy-1 (OPA1), and the mitochondrial fission proteins, dynamin-related peptide 1 (Drp1), mitochondrial fission protein 1 (Fis1), mitochondrial fission factor (Mff), and mitochondrial dynamics proteins of 49 and 51 kDa (MiD49/51).1,2 Until recently, the investigation of mitochondrial dynamics and morphology had been largely confined to non-cardiovascular cells. However, a number of recent experimental studies have suggested that changes in mitochondrial morphology may play a role in the cardiovascular system in the settings of vascular smooth cell proliferation, cardiac development and differentiation, stem cell differentiation, myocardial ischaemia–reperfusion injury (IRI), and heart failure (reviewed in 1 and 2).

Although the unique arrangement of mitochondria within the adult cardiomyocyte may limit their ability to move within the cell, the fact that the mitochondrial fusion and fission machinery is highly expressed in the adult myocardium would suggest that the mitochondrial fusion and fission proteins may have an important role to play in the adult heart. Whether mitochondrial dynamics are relevant to the post-mitotic adult heart is the subject of on-going investigation in several research laboratories, with recently published experimental studies implicating a role for the mitochondrial fission …
Methods of tophus assessment in clinical trials of chronic gout: a systematic literature review and pictorial reference guide
Authors: Nicola Dalbeth, Cameron Schauer, Patricia MacDonald, Fernando Perez-Ruiz, H Ralph Schumacher, Steve Hamburger, Hyon K Choi, Fiona M McQueen, Anthony Doyle, William J Taylor
Journal: Annals of the Rheumatic Diseases (2011)

To identify methods of tophus measurement for gout studies, summarise the properties of these methods and compile a detailed pictorial reference guide to demonstrate the methods.A systematic search strategy for methods of tophus measurement was formulated. For each method, papers were assessed by two reviewers to summarise information according to the specific components of the Outcomes Measures in Rheumatology (OMERACT) filter: feasibility, truth and discrimination. Detailed images were obtained to construct the reference guide.Eight methods of tophus measurement were identified: counting the total number of tophi, physical measurement using tape measure, physical measurement using Vernier callipers, digital photography, ultrasonography (US), MRI, CT and dual energy CT. Feasibility aspects of the methods are well documented. Physical measurement techniques are more feasible than advanced imaging methods, but do not allow for assessment of intra-articular tophi or for data storage and central reading. The truth aspect of the filter has been documented for many methods, particularly Vernier callipers, US, MRI and CT. Reliability of most methods has been reported as very good or excellent. Sensitivity to change has been reported for all methods except MRI and CT.A variety of methods of tophus assessment have been described for use in clinical trials of chronic gout. Physical measurement techniques (particularly the Vernier calliper method) and US measurement of tophus size appear to meet most aspects of the OMERACT filter.
The large lungs of elite swimmers: an increased alveolar number?
Authors: J Armour, PM Donnelly, PT Bye
Journal: European Respiratory Journal (1993)

In order to obtain further insight into the mechanisms relating to the large lung volumes of swimmers, tests of mechanical lung function, including lung distensibility (K) and elastic recoil, pulmonary diffusion capacity, and respiratory mouth pressures, together with anthropometric data (height, weight, body surface area, chest width, depth and surface area), were compared in eight elite male swimmers, eight elite male long distance athletes and eight control subjects. The differences in training profiles of each group were also examined. There was no significant difference in height between the subjects, but the swimmers were younger than both the runners and controls, and both the swimmers and controls were heavier than the runners. Of all the training variables, only the mean total distance in kilometers covered per week was significantly greater in the runners. Whether based on: (a) adolescent predicted values; or (b) adult male predicted values, swimmers had significantly increased total lung capacity ((a) 145 +/- 22%, (mean +/- SD) (b) 128 +/- 15%); vital capacity ((a) 146 +/- 24%, (b) 124 +/- 15%); and inspiratory capacity ((a) 155 +/- 33%, (b) 138 +/- 29%), but this was not found in the other two groups. Swimmers also had the largest chest surface area and chest width. Forced expiratory volume in one second (FEV1) was largest in the swimmers ((b) 122 +/- 17%) and FEV1 as a percentage of forced vital capacity (FEV1/FVC)% was similar for the three groups. Pulmonary diffusing capacity (DLCO) was also highest in the swimmers (117 +/- 18%). All of the other indices of lung function, including pulmonary distensibility (K), elastic recoil and diffusion coefficient (KCO), were similar. These findings suggest that swimmers may have achieved greater lung volumes than either runners or control subjects, not because of greater inspiratory muscle strength, or differences in height, fat free mass, alveolar distensibility, age at start of training or sternal length or chest depth, but by developing physically wider chests, containing an increased number of alveoli, rather than alveoli of increased size. However, in this cross-sectional study, hereditary factors cannot be ruled out, although we believe them to be less likely.
Two-Year Outcomes, Health Care Use, and Costs of Survivors of Acute Respiratory Distress Syndrome
Authors: Angela M. Cheung, Catherine M. Tansey, George Tomlinson, Natalia Diaz-Granados, Andrea Matté, Aiala Barr, Sangeeta Mehta, C. David Mazer, Cameron B. Guest, Thomas E. Stewart, Fatma Al-Saidi, Andrew B. Cooper, Deborah Cook, Arthur S. Slutsky, Margaret S. Herridge
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: Little is known about the long-term outcomes and costs of survivors of acute respiratory distress syndrome (ARDS).Objectives: To describe functional and quality of life outcomes, health care use, and costs of survivors of ARDS 2 yr after intensive care unit (ICU) discharge.Methods: We recruited a cohort of ARDS survivors from four academic tertiary care ICUs in Toronto, Canada, and prospectively monitored them from ICU admission to 2 yr after ICU discharge.Measurements: Clinical and functional outcomes, health care use, and direct medical costs.Results: Eighty-five percent of patients with ARDS discharged from the ICU survived to 2 yr; overall 2-yr mortality was 49%. At 2 yr, survivors continued to have exercise limitation although 65% had returned to work. There was no statistically significant improvement in health-related quality of life as measured by Short-Form General Health Survey between 1 and 2 yr, although there was a trend toward better physical role at 2 yr (p = 0.0586). Apart from emotional role and mental health, all other domains remained below that of the normal population. From ICU admission to 2 yr after ICU discharge, the largest portion of health care costs for a survivor of ARDS was the initial hospital stay, with ICU costs accounting for 76% of these costs. After the initial hospital stay, health care costs were related to hospital readmissions and inpatient rehabilitation.Conclusions: Survivors of ARDS continued to have functional impairment and compromised health-related quality of life 2 yr after discharge from the ICU. Health care use and costs after the initial hospitalization were driven by hospital readmissions and inpatient rehabilitation.
Effects of Initiating Carvedilol in Patients With Severe Chronic Heart Failure
Authors: Henry Krum, Ellen B. Roecker, Paul Mohacsi, Jean L. Rouleau, Michal Tendera, Andrew J. S. Coats, Hugo A. Katus, Michael B. Fowler, Milton Packer
Journal: JAMA (2003)

<h3>Context</h3> β-Blockers remain underused despite their established utility for improving outcome in heart failure. Concerns that initiation of treatment produces few immediate benefits and may have important risks may be deterring widespread use. <h3>Objective</h3> To evaluate the early effects of the β-blocker carvedilol in patients with severe heart failure. <h3>Design, Setting, and Patients</h3> Randomized, double-blind, placebo-controlled trial conducted from October 28, 1997, to March 20, 2000, at 334 hospital centers in 21 countries among 2289 patients with symptoms of heart failure at rest or with minimal exertion who were clinically euvolemic and had a left ventricular ejection fraction of less than 25%. <h3>Intervention</h3> Patients were randomly assigned to receive carvedilol, with start dosage of at 3.125 mg twice daily with uptitration to a target dosage of 25 mg twice daily (n = 1156), or placebo (n = 1133), in addition to their usual medications for heart failure. <h3>Main Outcome Measures</h3> Death, hospitalization, or permanent withdrawal from study drug, as well as adverse events during the first 8 weeks of treatment. <h3>Results</h3> The carvedilol group experienced no increase in cardiovascular risk but instead had fewer patients who died (19 vs 25; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.41-1.35); who died or were hospitalized (134 vs 153; HR, 0.85; 95% CI, 0.67-1.07); or who died, were hospitalized, or were permanently withdrawn from treatment (162 vs 188; HR, 0.83; 95% CI, 0.68-1.03). These effects were similar in direction and magnitude to those observed during the entire study, and were apparent particularly in the 624 patients with recent or recurrent decompensation or a very depressed left ventricular ejection fraction. Differences in favor of carvedilol became apparent as early as 14 to 21 days following initiation of treatment. Worsening heart failure was the only serious adverse event with a frequency greater than 2% and was reported with similar frequency in the placebo and carvedilol groups (6.4% vs 5.1%). <h3>Conclusions</h3> These data suggest that, in clinically euvolemic patients, the relation of benefit to risk during initiation of treatment with carvedilol is similar to that seen during long-term therapy with the drug. Our findings should provide the reassurance needed to encourage the high levels of use that are warranted by the results of long-term clinical trials.
Negative clinical trials in sarcoidosis: failed therapies or flawed study design?
Authors: David R. Moller
Journal: European Respiratory Journal (2014)

Negative results of clinical trials in sarcoidosis provide insights that can be used to rethink study design http://ow.ly/AWuWwIn this issue of the European Respiratory Journal, JUDSON et al. [1] report the results of a large clinical trial involving two new potential therapies in sarcoidosis, a subcutaneous anti-tumour necrosis factor (TNF) agent, golimumab, and a novel anti-p40 (a component of both interleukin (IL)-12 and IL-23) agent, ustekinumab.The rationale for the use of anti-TNF agents in sarcoidosis is compelling, as TNF plays a central role in granuloma formation [2].The use of anti-p40 (anti-IL-12/IL-23) also has a solid rationale based on the role of IL-12 in promoting T-helper (Th) type 1 immune responses and its upregulation in sarcoidosis.The role of the IL-23/Th17 pathways in sarcoidosis is less well established but the benefits of blocking IL-23 together with IL-12 is conceptually appealing in sarcoidosis [3].Given the clear rationale for testing these therapies in sarcoidosis, it is disappointing that neither therapy showed clinical benefit assessed by either primary or secondary end-points.These negative results follow a large trial of infliximab by many of these same investigators.In a randomised, placebo-controlled trial of infliximab in pulmonary sarcoidosis by BAUGHMAN et al. [4], there was a statistically significant 2.5% increase in forced vital capacity (FVC) % predicted with infliximab versus placebo and no significant differences for any of the major secondary end-points at 6 months.Although the authors suggest this was a robust response, healthcare payers (both corporations and governments) concluded that infliximab demonstrated only minimal improvement for patients with pulmonary sarcoidosis and cite this research as a reason to deny coverage of this therapy.Several studies find infliximab beneficial for progressive nonpulmonary manifestations of sarcoidosis [5,6], but in aggregate, these studies have not led to regulatory approval for infliximab in sarcoidosis in either Europe or the USA.
A multicenter clinical trial of epoetin beta for anemia of end-stage renal disease.
Authors: W M Bennett
Journal: Journal of the American Society of Nephrology (1991)

Patients with anemia of end-stage renal disease were studied for 36 weeks to determine efficacy, safety, and long-term benefits of epoetin beta administration. A total of 131 patients participated in the 12-week, double-blind, placebo-controlled portion of the multicenter study. For the first 6 weeks (fixed-dose period), patients were randomized to receive 100 U/kg of epoetin beta or placebo thrice weekly; in the second 6 weeks (dose-adjustment period), the dose of epoetin beta ranged from 50 to 150 U/kg thrice weekly. Of the 131 patients who entered the placebo-controlled period, 122 crossed over to a 24-week open-label period, where all patients received active drug and doses of epoetin beta could be individually titrated after the first 6 weeks. One hundred patients completed the 36-week study. In all phases of the study, epoetin beta was shown to produce a consistent, sustained increase in hemoglobin (baseline, 7.1 +/- 0.1 to 10.5 +/- 0.2 g/dL) and hematocrit (baseline, 21.5 to 32.7%), which virtually eliminated the need for packed red blood cell transfusions. Reticulocyte counts rose initially in response to epoetin beta and stabilized at levels higher than baseline throughout the remainder of the study period (baseline, 1.7 to 2.5%). The placebo group showed no change in these parameters during the double-blind period. Similar patterns of response were seen in the original placebo group after crossover to active drug (mean hemoglobin increase, 2.6 +/- 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)