tbuckley/cabot-search huggingface dataset:
Influence of Alternative Thresholds for Initiating HIV Treatment on Quality-Adjusted Life Expectancy: A Decision Model
Authors: R. Scott Braithwaite
Journal: Annals of Internal Medicine (2008)

Background: The optimal threshold for initiating HIV treatment is unclear. Objective: To compare different thresholds for initiating HIV treatment. Design: A validated computer simulation was used to weigh important harms from earlier initiation of antiretroviral therapy (toxicity, side effects, and resistance accumulation) against important benefits (decreased HIV-related mortality). Data Sources: Veterans Aging Cohort Study (5742 HIV-infected patients and 11 484 matched uninfected controls) and published reports. Target Population: Individuals with newly diagnosed chronic HIV infection and varying viral loads (10 000, 30 000, 100 000, and 300 000 copies/mL) and ages (30, 40, and 50 years). Time Horizon: Unlimited. Perspective: Societal. Intervention: Alternative thresholds for initiating antiretroviral therapy (CD4 counts of 200, 350, and 500 cells/mm3). Outcome Measures: Life-years and quality-adjusted life-years (QALYs). Results of Base-Case Analysis: Although the simulation was biased against earlier treatment initiation because it used an upper-bound assumption for therapy-related toxicity, earlier treatment increased life expectancy and QALYs at age 30 years regardless of viral load (life expectancies with CD4 initiation thresholds of 500, 350, and 200 cells/mm3 were 18.2 years, 17.6 years, and 17.2 years, respectively, for a viral load of 10 000 copies/mL and 17.3 years, 15.9 years, and 14.5 years, respectively, for a viral load of 300 000 copies/mL), and increased life expectancies at age 40 years if viral loads were greater than 30 000 copies/mL (life expectancies were 12.5 years, 12.0 years, and 11.4 years, respectively, for a viral load of 300 000 copies/mL). Results of Sensitivity Analysis: Findings favoring early treatment were generally robust. Limitations: Results favoring later treatment may not be valid. The findings may not be generalizable to women. Conclusion: This simulation suggests that earlier initiation of combination antiretroviral therapy is often favored compared with current recommendations.
The 10-s Maximal Sprint
Authors: Vanessa A. Bussau, Luis D. Ferreira, Timothy W. Jones, Paul A. Fournier
Journal: Diabetes Care (2006)

OBJECTIVE—To investigate whether a short maximal sprint can provide another means to counter the rapid fall in glycemia associated with moderate-intensity exercise in individuals with type 1 diabetes and therefore decrease the risk of early postexercise hypoglycemia. RESEARCH DESIGN AND METHODS—In the study, seven male subjects with type 1 diabetes injected their normal insulin dose and ate their usual breakfast. When their postprandial glycemia fell to ∼11 mmol/l, they pedaled at 40% ˙Vo2peak for 20 min on a cycle ergometer then immediately engaged in a maximal 10-s cycling sprint (sprint trial) or rested (control trial); the sprint and rest trials were administered in a counterbalanced order. RESULTS—Moderate-intensity exercise resulted in a significant fall (P &amp;lt; 0.05) in glycemia in both trials (means ± SE: 3.6 ± 0.5 vs. 3.1 ± 0.5 mmol/l for sprint and control, respectively). The subsequent short cycling sprint opposed a further fall in glycemia for 120 min, whereas in the absence of a sprint, glycemia decreased further (3.6 ± 1.22 mmol/l; P &amp;lt; 0.05) after exercise. The stabilization of glycemia in the sprint trial was associated with elevated levels of catecholamines, growth hormone, and cortisol. In contrast, these hormones remained at stable or near-stable levels in the control trial. Changes in insulin and free fatty acid levels were similar in the sprint and control trials. CONCLUSIONS—These results suggest that after moderate-intensity exercise, it is preferable for young individuals with insulin-treated, complication-free type 1 diabetes to engage in a 10-s maximal sprint to acutely oppose a further fall in glycemia than to only rest. The addition of the sprint after moderate-intensity exercise provides another means to reduce the risk of hypoglycemia in active individuals with type 1 diabetes.
Surveillance in patients with long-segment Barrett's oesophagus: a cost-effectiveness analysis
Authors: F Kastelein, S van Olphen, E W Steyerberg, M Sikkema, M C W Spaander, C W N Looman, E J Kuipers, P D Siersema, M J Bruno, E W de Bekker-Grob
Journal: Gut (2014)

<h3>Objective</h3> Surveillance is recommended for Barrett9s oesophagus (BO) to detect early oesophageal adenocarcinoma (OAC). The aim of this study was to evaluate the cost-effectiveness of surveillance. <h3>Design</h3> We included 714 patients with long-segment BO in a multicentre prospective cohort study and used a multistate Markov model to calculate progression rates from no dysplasia (ND) to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and OAC. Progression rates were incorporated in a decision-analytic model, including costs and quality of life data. We evaluated different surveillance intervals for ND and LGD, endoscopic mucosal resection (EMR), radiofrequency ablation (RFA) and oesophagectomy for HGD or early OAC and oesophagectomy for advanced OAC. The incremental cost-effectiveness ratio (ICER) was calculated in costs per quality-adjusted life-year (QALY). <h3>Results</h3> The annual progression rate was 2% for ND to LGD, 4% for LGD to HGD or early OAC and 25% for HGD or early OAC to advanced OAC. Surveillance every 5 or 4 years with RFA for HGD or early OAC and oesophagectomy for advanced OAC had ICERs of €5.283 and €62.619 per QALY for ND. Surveillance every five to one year had ICERs of €4.922, €30.067, €32.531, €41.499 and €75.601 per QALY for LGD. EMR prior to RFA was slightly more expensive, but important for tumour staging. <h3>Conclusions</h3> Based on a Dutch healthcare perspective and assuming a willingness-to-pay threshold of €35.000 per QALY, surveillance with EMR and RFA for HGD or early OAC, and oesophagectomy for advanced OAC is cost-effective every 5 years for ND and every 3 years for LGD.
Variation in end-stage renal disease patient outcomes
Authors: P Kurtin, A R Nissenson
Journal: Journal of the American Society of Nephrology (1993)

The size and expense of the ESRD program exceed all predictions made when the program was first initiated. Although the effectiveness of dialytic therapy is unquestioned, its value (quality/cost) is actively debated in this era of constricting resources. To better evaluate the quality of the ESRD program, it is essential to first define and quantitate the outcomes of dialytic care. Although mortality is a convenient outcome measure, it may be affected by many patient-specific as well as other factors that must be considered when evaluating and comparing new and existing technologies or advances. Quality of life is only beginning to be used in depth as an outcome measure, and much work is needed to standardize research methodology and thus move this area forward. The following review describes the current state of knowledge regarding outcomes of ESRD patients and proposes areas for future investigation, which should help increase the understanding of the value of the ESRD program to patients, providers, and payors.
Pharmacologic treatment of acute respiratory failure
Authors: K. L. So, E. P. Eijking, D. Gommers, E. de Buijzer, R. W. Beukenholdl, B. Lachmann, M. Sanchez, J. A. Cambronero, J. Lopez, E. Cerda, J. M. Rodriguez, J. Rubio, S. Rogero, A. Nunez, R. B. Carrington da Costa, A. C. Falcão, J. Pimentel, A. Rebelo, J. Janeiro da Costa, J. P. A. Sousa, V. Fernandes, A. Simões, M. M. Carmona, P. Plaisance, D. Payen, M. -D. Schaller, G. Domenighetti, P. M. Suter, M. -Ch. Laverrière, R. Ritz, R. Ruffmann, Cl. Perret, M. Belghith, F. Brunet, J. P. Mira, J. J. Lanore, B. Renaud, I. Hamy, S. Schlumberger, P. Toulon, J. F. Dhainaut
Journal: Intensive Care Medicine (1992)
Heat stress does not exacerbate tennis-induced alterations in physical performance
Authors: Olivier Girard, Ryan J Christian, Sébastien Racinais, Julien D Périard
Journal: British Journal of Sports Medicine (2014)

To assess the time course of changes in physical performance in response to match-play tennis under heat stress.Two matches consisting of 20 min of effective playing time (2×10 min segments) were played in COOL (∼102 min; ∼22°C and 70% relative humidity (RH)) and HOT (∼119 min; ∼36°C and 35% RH) environments. Repeated-sprint ability (3×15 m, 15 s rest), 15 m sprint time with a direction change (180°), vertical jump height (squat and countermovement jumps) and leg stiffness (multirebound jumps) were assessed in 12 competitive male players prematch, midmatch and postmatch, and 24 and 48 h after match completion.During the repeated-sprint ability test, initial (+2.3% and +3.1%) and cumulated sprint (+1.5% and +2.8%) times increased from prematch to midmatch and postmatch, respectively (p<0.001), while the sprint decrement score did not change. Match-play tennis induced a slowing (average of both conditions: +1.1% and +1.3% at midmatch and postmatch time points; p=0.05) of 15 m sprint time with direction change. Compared with prematch, leg stiffness (-6.4% and -6.5%; p<0.001) and squat jump height (-1.5% and -2.4%; p=0.05), but not countermovement jump height (-0.7% and -1.3%; p>0.05), decreased midmatch and postmatch, respectively, regardless of the condition. Complete recovery in all physical performance markers occurred within 24 h.In tennis, match-related fatigue is characterised by impaired repeated-sprint ability, explosive power and leg stiffness at midmatch and postmatch, with values restored to prematch baseline 24 h into recovery. In addition, physical performance responses (match and recovery kinetics) are identical when competing in cool and hot environments.
SEGMENTAL RESPONSE OF THE MACROPHAGE PLASMA MEMBRANE TO A PHAGOCYTIC STIMULUS
Authors: Frank M. Griffin, Samuel C. Silverstein
Journal: The Journal of Experimental Medicine (1974)

A method of attaching mouse RBCs to mouse macrophages is described. Both cell types were coated with rabbit anti-mouse macrophage F(ab')2, and cross-linkage of cells was effected with sheep F(ab')2 directed against rabbit F(ab')2. 98% of macrophages attached an average of 11 RBCs each. Attachment occurred at 37°C and was stable for at least 4 h. Less than 0.1% of macrophages ingested RBCs under these conditions. Latex particles and opsonized pneumococci were ingested as avidly by RBC-coated macrophages as by native macrophages. Ingestion of these particles did not prompt ingestion of attached RBCs. When anti-RBC IgG was added, however, over 90% of macrophages ingested an average of six RBCs each. Thus, ingestion of one particle does not trigger generalized phagocytosis of all particles attached to the cell's plasma membrane, and the phagocytic stimulus is confined to the segment of the cell's plasma membrane immediately adjacent to the particle being ingested.
Long-term decrease in serum N-terminal propeptide of type III procollagen in patients with chronic hepatitis C treated with interferon alfa
Authors: Takeaki Suou, Keiko Hosho, Yukihiro Kishimoto, Yasushi Horie, Hironaka Kawasaki
Journal: Hepatology (1995)

To evaluate the effect of interferon alfa (IFN-alpha) on the hepatic extracellular matrix, we investigated the changes in serum N-terminal propeptide of type III procollagen during and after 4 months of INF-alpha treatment in 178 treated and 45 nontreated patients with chronic hepatitis C. Serum pretreatment levels in nonresponders were significantly higher than those in long-term and short-term responders, but those levels were not different in the latter two groups. Serum propeptide levels decreased significantly during and after IFN-alpha therapy in the treated patients, although those levels were unchanged in the nontreated patients. This decrease was sustained for 12 months after IFN-alpha was completed not only in long-but also in short-term responders and nonresponders. Serum propeptide levels decreased in those with elevated pretreatment levels, but not in those with normal initial levels, whereas serum transaminase levels decreased similarly in both groups. The changes in serum propeptide levels during and after treatment were more closely correlated with the initial levels compared with those in serum transaminase levels. These results suggested that IFN-alpha treatment induces the long-term suppression of active fibrogenesis in chronic hepatitis C independent of antiviral and anti-necroinflammatory effects, thus preventing progression to cirrhosis.
A Novel Role for Extracellular Signal-Regulated Kinase 5 and Myocyte Enhancer Factor 2 in Medulloblastoma Cell Death
Authors: Lisa-Marie Sturla, Christopher W. Cowan, Lillian Guenther, Robert C. Castellino, John Y.H. Kim, Scott L. Pomeroy
Journal: Cancer Research (2005)

Abstract Expression of the neurotrophin-3 receptor, tyrosine kinase C (TrkC), is associated with favorable prognosis in medulloblastoma patients. This may be due to increased tumor apoptosis induced by TrkC activation. Neurotrophin-3/TrkC–induced apoptosis is inhibited by the mitogen-activated protein (MAP) kinase (MAPK) pharmacologic antagonists SB203580 and PD98059. In addition to extracellular signal-regulated kinase (ERK)-1/2, PD98059 also inhibits the more recently identified neurotrophin-responsive MAPK, ERK5 (big MAPK 1). In the present study, we investigate the contribution of ERK5 and its target myocyte enhancer factor 2 (MEF2) to neurotrophin-3/TrkC–induced medulloblastoma cell death. Neurotrophin-3 not only enhanced ERK5 phosphorylation but also significantly enhanced the transcriptional activity of MEF2, a specific target of ERK5. Overexpression of both ERK5 and MEF2 induced a statistically significant increase in cell death of neurotrophin-3–responsive and nonresponsive medulloblastoma cell lines (Daoy-trkC and Daoy) and primary cultures of patched heterozygous mouse medulloblastomas. Only those cells expressing MAP/ERK kinase 5 (MEK5) plus ERK5 or MEF2 constructs underwent apoptosis, indicating that overexpression of either is sufficient to induce medulloblastoma cell death. Expression of a dominant-negative MEF2 or small interfering RNA for the ERK5 activator, MEK5, significantly inhibited neurotrophin-3–induced cell death. The dominant-negative MEF2 construct also blocked MEK5/ERK5-induced cell death, supporting a role for MEF2 downstream of ERK5. Coimmunoprecipitation studies revealed direct interaction of phosphorylated ERK5 with MEF2 in response to neurotrophin-3. Our investigation of the mechanism of neurotrophin-3/TrkC–induced apoptosis has identified a novel role for both MEK5/ERK5 and MEF2 in cell death, suggesting that these molecules can be exploited to induce apoptosis in both TrkC-expressing and nonexpressing medulloblastoma cells.
Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study
Authors: Mohammad Movahedi, D. Timothy Bishop, Finlay Macrae, Jukka-Pekka Mecklin, Gabriela Moeslein, Sylviane Olschwang, Diana Eccles, D. Gareth Evans, Eamonn R. Maher, Lucio Bertario, Marie-Luise Bisgaard, Malcolm G. Dunlop, Judy W.C. Ho, Shirley V. Hodgson, Annika Lindblom, Jan Lubinski, Patrick J. Morrison, Victoria Murday, Raj S. Ramesar, Lucy Side, Rodney J. Scott, Huw J.W. Thomas, Hans F. Vasen, John Burn, John C. Mathers
Journal: Journal of Clinical Oncology (2015)

Purpose In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This prospective study investigated the association between body mass index and cancer risk in patients with Lynch syndrome (LS). Patients and Methods Participants with LS were recruited to the CAPP2 study, in which they were randomly assigned to receive aspirin 600 mg per day or aspirin placebo, plus resistant starch 30 g per day or starch placebo (2 × 2 factorial design). Mean intervention period was 25.0 months, and mean follow-up was 55.7 months. Results During follow-up, 55 of 937 participants developed CRC. For obese participants, CRC risk was 2.41× (95% CI, 1.22 to 4.85) greater than for underweight and normal-weight participants (reference group), and CRC risk increased by 7% for each 1-kg/m 2 increase in body mass index. The risk of all LS-related cancers in obese people was 1.77× (95% CI, 1.06 to 2.96; P = .03) greater than for the reference group. In subgroup analysis, obesity was associated with 3.72× (95% CI, 1.41 to 9.81) greater CRC risk in patients with LS with MLH1 mutation, but no excess risk was observed in those with MSH2 or MSH6 mutation (P = .5). The obesity-related excess CRC risk was confined to those randomly assigned to the aspirin placebo group (adjusted hazard ratio, 2.75; 95% CI, 1.12 to 6.79; P = .03). Conclusion Obesity is associated with substantially increased CRC risk in patients with LS, but this risk is abrogated in those taking aspirin. Such patients are likely to benefit from obesity prevention and/or regular aspirin.
The Streptococcal Superantigen Smez Exhibits Wide Allelic Variation, Mosaic Structure, and Significant Antigenic Variation
Authors: Thomas Proft, S. Louise Moffatt, Kylie D. Weller, A. Paterson, Diana Martin, John D. Fraser
Journal: The Journal of Experimental Medicine (2000)

The frequencies of the newly identified streptococcal superantigen genes smez, spe-g, and spe-h were determined in a panel of 103 clinical isolates collected between 1976 and 1998 at various locations throughout New Zealand. smez and spe-g were found in every group A Streptococcus (GAS) isolate, suggesting a chromosomal location. The spe-h gene was found in only 24% of the GAS isolates and is probably located on a mobile DNA element. The smez gene displays extensive allelic variation and appears to be in linkage equilibrium with the M/emm type. 22 novel smez alleles were identified from 21 different M/emm types in addition to the already reported alleles smez and smez-2 with sequence identities between 94.5 and 99.9%. Three alleles are nonfunctional due to a single base pair deletion. The remaining 21 alleles encode distinct SMEZ variants. The mosaic structure of the smez gene suggests that this polymorphism has arisen from homologous recombination events rather than random point mutation. The recently resolved SMEZ-2 crystal structure shows that the polymorphic residues are mainly surface exposed and scattered over the entire protein. The allelic variation did not affect either Vβ specificity or potency, but did result in significant antigenic differences. Neutralizing antibody responses of individual human sera against different SMEZ variants varied significantly. 98% of sera completely neutralized SMEZ-1, but only 85% neutralized SMEZ-2, a very potent variant that has not yet been found in any New Zealand isolate. SMEZ-specific Vβ8 activity was found in culture supernatants of 66% of the GAS isolates, indicating a potential base for the development of a SMEZ targeting vaccine.
PWE-005 High resolution anorectal manometry: first study establishing normal values in healthy volunteers: Abstract PWE-005 Table 1
Authors: J M Burke, W Jackson, M M Withers, H O'Grady, G S Duthie
Journal: Gut (2012)

<h3>Introduction</h3> High Resolution Anorectal Manometry (HRAM) combined with interpretive software allows for the interpolation of manometric recordings into highly detailed topographical plots of intraluminal pressure events. HRAM has previously been shown to correlate highly with conventional water perfused manometry measurements.<sup>1</sup> This preliminary study is the first report establishing HRAM pressures in healthy volunteers. The advantages of the detection of pressure changes over a longer length of the anal canal have already been shown to improve accuracy and the detection of abnormalities in the anorectum.<sup>2</sup> <h3>Methods</h3> HRAM was performed using the Medical Measurement System (Enschede, Netherlands) consisting of an 8-channel HRAM catheter with sensors spaced at 0.8 cm intervals. Pressure data are displayed in topographic form using Medical Measurement System analysis software that is integrated into the system. Measurements of anal sphincter pressure at rest, cough, during voluntary squeeze, endurance squeeze and pushdown were evaluated. Volunteers also completed a questionnaire which provided a Wexner score. <h3>Results</h3> A total of 20 healthy volunteers (11 Female, 9 Male) with a mean age of 40 (range 19–60) constituted the study population. The Wexner scores ranged from 0 to 1 (median 0). <h3>Conclusion</h3> These preliminary measurements of HRAM pressures in healthy volunteers could serve as a valuable resource of normative data when performing HRAM studies in disease specific groups such as incontinence and constipation. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Jones MP</b>, Post J, Crowell MD. High-resolution manometry in the evaluation of anorectal disorders: a simultaneous comparison with water-perfused manometry. <i>Am J Gastroenterol</i> 2007;<b>102</b>:850–5. 2. <b>Rao SS</b>. Advances in diagnostic assessment of fecal incontinence and dyssynergic defecation <i>Clin Gastroenterol Hepatol</i> 2010;<b>8</b>:910–19.
Modulation of Glutamate Receptors: Molecular Mechanisms and Functional Implications
Authors: J T Wroblewski, W Danysz
Journal: The Annual Review of Pharmacology and Toxicology (1989)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Changing Impact of Modifiable Risk Factors on the Incidence of Major Outcomes of Type 1 Diabetes
Authors: Rachel G. Miller, Aaron M. Secrest, Demetrius Ellis, Dorothy J. Becker, Trevor J. Orchard
Journal: Diabetes Care (2013)

The incidence of type 1 diabetes complications appears to be decreasing, but relative contributions of risk factors are unclear. We thus estimated the effect of modifiable risk factors on the incidence of a composite end point, major outcomes of diabetes (MOD).The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study was used to derive two cohorts based on diabetes diagnosis year (1960-1969 and 1970-1980). Baseline exam data in the current analysis for the 1960s group were collected in 1986-1988 and for the 1970s in 1996-1998. Each group was followed for 8 years for MOD incidence (diabetes-related death, myocardial infarction, revascularization procedure/blockage ≥50%, stroke, end-stage renal disease, blindness, and amputation). Assessed risk factors include the following: HbA1c, hypertension, microalbuminuria, BMI, hypercholesterolemia, and smoking. Accelerated failure time models were used to estimate the acceleration factor.MOD incidence decreased in the 1970s cohort (15.8% [95% CI 11.6-21.4]) compared with the 1960s (22.6% [17.0-29.1]) over the 8-year follow-up (P = 0.06). Hypertension and microalbuminuria were associated with significantly accelerated MOD incidence in both cohorts (P < 0.01 for both). High HbA1c (P = 0.0005), hypercholesterolemia (P = 0.01), and current smoking (P = 0.003) significantly accelerated the incidence of MOD in the 1960s but not 1970s cohort. BMI was not associated with MOD in either cohort.These results suggest that hypertension and microalbuminuria remain important predictors of complications that are not being adequately addressed.