tbuckley/cabot-search huggingface dataset:
Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children
Authors: E von Mutius, S Illi, T Hirsch, W Leupold, U Keil, Sk Weiland
Journal: European Respiratory Journal (1999)

The role of repeated infections early in life in the development of childhood asthma and allergies has not been clarified. The aim of this study was to investigate the effect of repeated episodes of fever and antibiotic treatments during the first years of life on the prevalence of asthma, bronchial hyperresponsiveness (BHR), and atopy at school age in a representative population. Random samples of schoolchildren aged 5-7 yrs (n=7,545) and 9-11 yrs (n=7,498) were studied using the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol. To assess the prevalence of disease and early childhood exposures, parental questionnaires were administered (response rates 82.2% and 85.3%, respectively). In addition, children underwent skin prick tests, hypertonic saline challenge and blood sampling for the measurement of serum immunoglobulin (Ig)E. Repeated episodes of fever and antibiotic treatment in early life were strongly associated with the prevalence of asthma (odds ratio (OR)=7.95; 95% confidence interval (CI) 6.02-10.50) and current wheeze at school age. Within asthmatic children the number of fever episodes and antibiotic courses were strongly inversely related to the prevalence of atopy (OR=0.25; 95% CI 0.11-0.54 for skin test reactivity) and BHR (OR=0.31; 95% CI 0.10-0.92). Furthermore, asthmatic children with recurrent early childhood infections were at a lower risk of being symptomatic at school age. When considering atopic and nonatopic asthmatic children separately, the highest risk of asthma with repeated early childhood infections was found for nonatopic asthma (OR=24.29; 95% Cl 11.86-49.76). These findings suggest that a subgroup of children with a triggering or inducing of asthmatic symptoms through repeated early childhood infections exists within the "asthma syndrome" which has a better prognosis and is less related to the atopic phenotype.
Equality in Lynch Syndrome Screening: Why Should We Hold Patients With Endometrial Cancer to a Different Standard?
Authors: Jessica Moline, Charis Eng
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: In their recently published study, Buchanan et al 1 proposed a population screening strategy for the identification of Lynch syndrome in patients with endometrial cancer. In their algorithm, they showed a cost savings benefit with the addition of MLH1 promoter methylation for tumors demonstrating a lack of MLH1/ PMS2 expression. We agree that methylation testing is cost-effective and a necessary step in triaging patients for genetic counseling and genetic testing. However, the authors also determined that screening for women diagnosed before age 60 years optimizes identification of Lynch syndrome. We would like to comment on the pitfalls of using age as a screening criterion in the clinical setting. In this study cohort, only three of 22 women (14%) with pathogenic mismatch repair mutations were older than age 60 years at the timeofdiagnosis. 1 Thisproportionissignificantlylowerthaninother population-based studies. Hampel et al 2,3 found five of 13 women (38%) with Lynch syndrome were diagnosed after age 60 years. In a studybyLeenenetal, 4 threeofsevenwomenwithgermlinemutations (43%) were older than age 60 years. The inherent bias in the present study has likely skewed thefinal cost per carrier in this population. As we have shown, the clinical practice of implementing tumor screeningforLynchsyndromediffersfromresearchpractices. 5 Inour 3 years of screening on the basis of age and molecular characteristics, 27 eligible patients were overlooked by pathologists for screening. Using a universal screening approach, no patients were missed. Eliminatingastepfromthepathologists’workflowtodetermineifapatient meetsscreeningcriteriacutsdownonthechanceforerrorandstreamlines processes. Wealsoraisethisquestion:whyshouldweplacestringentcriteria on screening for endometrial cancers when universal screening for coloncancersiswidelyaccepted?Inamulticenteranalysisofuniversal tumor screening in colorectal cancer, 26 of 82 individuals (32%) with Lynch syndrome were diagnosed after age 60 years. 6 If we look at published data for endometrial cancer, we see relatively the same age distribution (38% to 42% of patients diagnosed after age 60 years). 2,4
Antitumor Activity and Clinical Pharmacology of Sulofenur in Ovarian Cancer
Authors: C. W. Taylor, D. S. Alberts, Y.-M. Peng, T. M. McCloskey, M. Matzner, D. J. Roe, P. M. Plezia, G. B. Grindey, M. Hamilton, D. Seitz
Journal: JNCI Journal of the National Cancer Institute (1992)

Sulofenur is a diarylsulfonylurea with demonstrated antitumor activity in patients with advanced epithelial ovarian cancer refractory to standard chemotherapy. The dose-limiting toxic effects observed in phase I clinical trials have been anemia and methemoglobinemia, resulting in cyanosis.The purposes of this study were to further define the response rate, toxic effects, and pharmacokinetics and pharmacodynamics of sulofenur in patients with advanced ovarian cancer.We conducted a phase II trial of sulofenur at a dose of 800 mg/m2 per day in 35 patients with stage III or IV ovarian cancer refractory to standard chemotherapy. Pharmacokinetics and pharmacodynamics were analyzed by comparing sulofenur parent and metabolite plasma levels with methemoglobin levels.Partial responses lasting 6.5-18 weeks occurred in four (15%; 95% confidence interval = 4%-35%) of the 26 patients assessable for response. In addition, 42% (11) of the assessable patients had prolonged stable disease (median, 20 weeks). The first nine patients received sulofenur as a daily oral dose for 14 days, with a 21-day treatment cycle. However, they developed substantial anemia and methemoglobinemia. As a result, the next 26 patients received sulofenur daily for 5 days followed by 2 days of rest for 3 consecutive weeks, with a 28-day treatment cycle (5/2-day schedule). Preclinical models predicted that 2 days of rest would decrease toxicity while maintaining antitumor activity. Patients treated with the 5/2-day schedule had relatively less severe anemia and methemoglobinemia and needed fewer red blood cell transfusions (31% versus 78% of patients), but 31% still required dose reductions because of these toxic effects. The hydroxy and keto metabolites of sulofenur had prolonged plasma half-lives relative to the parent compound, and the difference was statistically significant. In addition, the correlations of metabolite concentrations with methemoglobin levels were higher than the correlation of sulofenur concentrations with methemoglobin levels, and those differences were statistically significant.We conclude that sulofenur has modest clinical activity in heavily pretreated patients with ovarian cancer.The toxic effects of anemia and methemoglobinemia may limit the ultimate clinical utility of diarylsulfonylureas until less toxic derivatives with alternate metabolic pathways can be identified.
Improving survival in idiopathic pulmonary arterial hypertension: revisiting the "kingdom of the near-dead"
Authors: S Mehta
Journal: Thorax (2005)

Recent advances in the treatment of idiopathic PAH have resulted in increased survival

Idiopathic pulmonary arterial hypertension (PAH), formerly known as primary pulmonary hypertension, is characterised by raised pulmonary artery pressure and pulmonary vascular resistance in the absence of underlying significant cardiopulmonary or other medical disease. Idiopathic PAH is a progressive disorder that usually culminates in right ventricular failure and death. Moreover, patients with idiopathic PAH are often severely limited on exertion by dyspnoea and fatigue, and thus suffer from a poor quality of life.

Despite clinical recognition of idiopathic PAH for more than 100 years, there have been few effective therapeutic options until recently. Given the previous absence of effective pharmacological therapy, surgical removal of the disease by lung transplantation has been an important therapeutic option for patients with idiopathic PAH. Lung transplantation is associated with rapid and sustained improvement in pulmonary haemodynamics.1 Moreover, in individual patients with idiopathic PAH who do not respond to medical treatment, timely lung transplantation will often be associated with improved survival even though long term survival after lung transplantation remains poor.2,3

One of the first long term pharmacological approaches used for treating idiopathic PAH was systemic anticoagulation. In patients with idiopathic PAH, pulmonary microvascular thrombosis is present histologically and there is laboratory evidence of a procoagulant haematological state.4,5 Moreover, both retrospective and non-randomised cohort studies have suggested a survival benefit of systemic anticoagulation in idiopathic PAH.6,7 Although not formally studied in a randomised controlled trial, systemic anticoagulation is recommended for the majority of patients with PAH in the absence of a clear contraindication based on assessment of individual bleeding risk.8

Ongoing basic biological and clinical research has led to tremendous advances in our understanding of the pathobiology of idiopathic PAH. Moreover, an increasing number of …
Concordant Restoration of Ovarian Function and Mood in Perimenopausal Depression
Authors: Robert C Daly, Merry A Danaceau, David R Rubinow, Peter J Schmidt
Journal: American Journal of Psychiatry (2003)

Despite reports of estradiol's therapeutic efficacy in perimenopausal depression, the relationship between ovarian function and mood in perimenopausal depression remains unclear. The purpose of this study was to examine changes in mood and pituitary-ovarian axis function in women exhibiting perimenopausal depression.Depression ratings (from the Center for Epidemiologic Studies-Depression Scale [CES-D Scale]) and follicle-stimulating hormone (FSH) plasma levels of depressed perimenopausal women (N=110) attending a menopause clinic were obtained at baseline and after a 6-week screening period.Eighteen women experienced an improvement in depression (50% decline in CES-D Scale scores) at week 6, which was associated with a significant decrease in FSH plasma levels (baseline: mean=73.3 IU/liter [SD=42.0]; week 6: mean=42.2 IU/liter [SD=28.6]). Similarly, those subjects experiencing a 50% drop in FSH plasma levels had significant decreases in CES-D Scale scores (baseline: mean=23.3 [SD=6.8]; week 6: mean=18.1 [SD=10.9]). However, between women with CES-D Scale scores > or = 15 and those with CES-D Scale scores <15, no significant differences in FSH levels were observed either at baseline (mean=65.5 IU/liter [SD=35.7] and 60.9 IU/liter [SD=34.9], respectively) or at week 6 (mean=56.2 IU/liter [SD=36.6] and 51.5 IU/liter [SD=34.2]).Mood variability in women with perimenopausal depression may reflect episodic alterations in ovarian function that are best detected by longitudinal study designs.
Challenging and Unusual Cases
Authors: Faheez Mohamed, Kaiumarz Sethna, Dominique Elias, Paul H. Sugarbaker
Journal: Journal of Clinical Oncology (2003)

Article Tools DIAGNOSIS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.06.167 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12663738 Challenging and Unusual Cases CASE 3. PERITONEAL CYSTIC MESOTHELIOMA Faheez MohamedxFaheez MohamedSearch for articles by this author , Kaiumarz SethnaxKaiumarz SethnaSearch for articles by this author , Dominique EliasxDominique EliasSearch for articles by this author , Paul H. SugarbakerxPaul H. SugarbakerSearch for articles by this author Show More The Washington Cancer Institute, Washington Hospital Center, Washington, DC; and the Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, France https://doi.org/10.1200/JCO.2003.06.167 First Page Full Text PDF Figures and Tables © 2003 by American Society of Clinical Oncology
Re-engineering systems for the treatment of depression in primary care: cluster randomised controlled trial
Authors: Allen J Dietrich, Thomas E Oxman, John W Williams, Herbert C Schulberg, Martha L Bruce, Pamela W Lee, Sheila Barry, Patrick J Raue, Jean J Lefever, Moonseong Heo, Kathryn Rost, Kurt Kroenke, Martha Gerrity, Paul A Nutting
Journal: BMJ (2004)

To test the effectiveness of an evidence based model for management of depression in primary care with support from quality improvement resources.Cluster randomised controlled trial.Five healthcare organisations in the United States and 60 affiliated practices.405 patients, aged > or = 18 years, starting or changing treatment for depression.Care provided by clinicians, with staff providing telephone support under supervision from a psychiatrist.Severity of depression at three and six months (Hopkins symptom checklist-20): response to treatment (> or = 50% decrease in scores) and remission (score of < 0.5).At six months, 60% (106 of 177) of patients in intervention practices had responded to treatment compared with 47% (68 of 146) of patients in usual care practices (P = 0.02). At six months, 37% of intervention patients showed remission compared with 27% for usual care patients (P = 0.014). 90% of intervention patients rated their depression care as good or excellent at six months compared with 75% of usual care patients (P = 0.0003).Resources such as quality improvement programmes can be used effectively in primary care to implement evidence based management of depression and improve outcomes for patients with depression.
The Toxic Effects of Cigarette Additives. Philip Morris' Project Mix Reconsidered: An Analysis of Documents Released through Litigation
Authors: Marcia S. Wertz, Thomas Kyriss, Suman Paranjape, Stanton A. Glantz
Journal: PLoS Medicine (2011)

In 2009, the promulgation of US Food and Drug Administration (FDA) tobacco regulation focused attention on cigarette flavor additives. The tobacco industry had prepared for this eventuality by initiating a research program focusing on additive toxicity. The objective of this study was to analyze Philip Morris' Project MIX as a case study of tobacco industry scientific research being positioned strategically to prevent anticipated tobacco control regulations.We analyzed previously secret tobacco industry documents to identify internal strategies for research on cigarette additives and reanalyzed tobacco industry peer-reviewed published results of this research. We focused on the key group of studies conducted by Phillip Morris in a coordinated effort known as "Project MIX." Documents showed that Project MIX subsumed the study of various combinations of 333 cigarette additives. In addition to multiple internal reports, this work also led to four peer-reviewed publications (published in 2001). These papers concluded that there was no evidence of substantial toxicity attributable to the cigarette additives studied. Internal documents revealed post hoc changes in analytical protocols after initial statistical findings indicated an additive-associated increase in cigarette toxicity as well as increased total particulate matter (TPM) concentrations in additive-modified cigarette smoke. By expressing the data adjusted by TPM concentration, the published papers obscured this underlying toxicity and particulate increase. The animal toxicology results were based on a small number of rats in each experiment, raising the possibility that the failure to detect statistically significant changes in the end points was due to underpowering the experiments rather than lack of a real effect.The case study of Project MIX shows tobacco industry scientific research on the use of cigarette additives cannot be taken at face value. The results demonstrate that toxins in cigarette smoke increase substantially when additives are put in cigarettes, including the level of TPM. In particular, regulatory authorities, including the FDA and similar agencies elsewhere, could use the Project MIX data to eliminate the use of these 333 additives (including menthol) from cigarettes.
Phase II Study of Cetuximab As First-Line Single-Drug Therapy in Patients With Unresectable Squamous Cell Carcinoma of the Skin
Authors: Eve Maubec, Peter Petrow, Isabelle Scheer-Senyarich, Pierre Duvillard, Ludovic Lacroix, Julien Gelly, Agnès Certain, Xavier Duval, Béatrice Crickx, Valérie Buffard, Nicole Basset-Seguin, Pierre Saez, Anne-Bénédicte Duval-Modeste, Henri Adamski, Sandrine Mansard, Florent Grange, Anne Dompmartin, Sandrine Faivre, France Mentré, Marie-Françoise Avril
Journal: Journal of Clinical Oncology (2011)

To evaluate the efficacy and safety of cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), as a first-line monotherapy in patients with unresectable squamous cell carcinoma of the skin (SCCS).Thirty-six patients received cetuximab (initial dose of 400 mg/m(2) followed by subsequent weekly doses of 250 mg/m(2)) for at least 6 weeks with a 48-week follow-up. The primary end point was the disease control rate (DCR) at 6 weeks (according to Response Evaluation Criteria in Solid Tumors [RECIST] criteria). Secondary end points included best response rate, overall survival, progression-free survival (PFS), and toxicity assessment. Association of treatment efficacy with RAS mutations or FcγR genotypes was investigated.Median age of the study population was 79 years. DCR at 6 weeks was obtained in 25 of 36 patients (69%; 95% CI, 52% to 84%) of the intention-to-treat population. The best responses were eight partial responses and two complete responses. There were no cetuximab-related deaths. There were three related serious adverse events: two grade 4 infusion reactions and one grade 3 interstitial pneumopathy. Grade 1 to 2 acne-like rash occurred in 78% of patients and was associated with prolonged PFS. One HRAS mutation was identified. Combined FcγRIIa-131H/H and/or FcγRIIIa-158V/V polymorphisms were not associated with the clinical outcomes.As a first-line treatment in patients with unresectable SCCS, cetuximab achieved 69% DCR. A randomized phase III trial is warranted to confirm that cetuximab may be considered as a therapeutic option especially in elderly patients. The low frequency of RAS mutations in SCCS makes SCCS tumors attractive for EGFR inhibition.
Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised controlled trial
Authors: Heather J Zar, Mark F Cotton, Stanzi Strauss, Janine Karpakis, Gregory Hussey, H Simon Schaaf, Helena Rabie, Carl J Lombard
Journal: BMJ (2006)

<b>Objectives</b> To investigate the impact of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV. <b>Design</b> Two centre prospective double blind placebo controlled trial. <b>Participants</b> Children aged ≥8 weeks with HIV. <b>Interventions</b> Isoniazid or placebo given with co-trimoxazole either daily or three times a week. <b>Setting</b> Two tertiary healthcare centres in South Africa. <b>Main outcome measures</b> Mortality, incidence of tuberculosis, and adverse events. <b>Results</b> Data on 263 children (median age 24.7 months) were available when the data safety monitoring board recommended discontinuing the placebo arm; 132 (50%) were taking isoniazid. Median follow-up was 5.7 (interquartile range 2.0-9.7) months. Mortality was lower in the isoniazid group than in the placebo group (11 (8%) <i>v</i> 21 (16%), hazard ratio 0.46, 95% confidence interval 0.22 to 0.95, P=0.015) by intention to treat analysis. The benefit applied across Centers for Disease Control clinical categories and in all ages. The reduction in mortality was similar in children on three times a week or daily isoniazid. The incidence of tuberculosis was lower in the isoniazid group (5 cases, 3.8%) than in the placebo group (13 cases, 9.9%) (hazard ratio 0.28, 0.10 to 0.78, P=0.005). All cases of tuberculosis confirmed by culture were in children in the placebo group. <b>Conclusions</b> Prophylaxis with isoniazid has an early survival benefit and reduces incidence of tuberculosis in children with HIV. Prophylaxis may offer an effective public health intervention to reduce mortality in such children in settings with a high prevalence of tuberculosis. <b>Trial registration.</b> Clinical Trials NCT00330304
Hepatic Insulin Clearance Is Closely Related to Metabolic Syndrome Components
Authors: Olga Pivovarova, Wolfgang Bernigau, Thomas Bobbert, Frank Isken, Matthias Möhlig, Joachim Spranger, Martin O. Weickert, Martin Osterhoff, Andreas F.H. Pfeiffer, Natalia Rudovich
Journal: Diabetes Care (2013)

Insulin clearance is decreased in type 2 diabetes mellitus (T2DM) for unknown reasons. Subjects with metabolic syndrome are hyperinsulinemic and have an increased risk of T2DM. We aimed to investigate the relationship between hepatic insulin clearance (HIC) and different components of metabolic syndrome and tested the hypothesis that HIC may predict the risk of metabolic syndrome.Individuals without diabetes from the Metabolic Syndrome Berlin Brandenburg (MeSyBePo) study (800 subjects with the baseline examination and 189 subjects from the MeSyBePo recall study) underwent an oral glucose tolerance test (OGTT) with assessment of insulin secretion (insulin secretion rate [ISR]) and insulin sensitivity. Two indices of HIC were calculated.Both HIC indices showed lower values in subjects with metabolic syndrome (P < 0.001) at baseline. HIC indices correlate inversely with waist circumference, diastolic blood pressure, fasting glucose, triglycerides, and OGTT-derived insulin secretion index. During a mean follow-up of 5.1 ± 0.9 years, 47 individuals developed metabolic syndrome and 33 subjects progressed to impaired glucose metabolism. Both indices of HIC showed a trend of an association with increased risk of metabolic syndrome (HICC-peptide odds ratio 1.13 [95% CI 0.97-1.31], P = 0.12, and HICISR 1.38 [0.88-2.17], P = 0.16) and impaired glucose metabolism (HICC-peptide 1.12 [0.92-1.36], P = 0.26, and HICISR 1.31 [0.74-2.33] P = 0.36), although point estimates reached no statistical significance.HIC was associated with different components of metabolic syndrome and markers of insulin secretion and insulin sensitivity. Decreased HIC may represent a novel pathophysiological mechanism of the metabolic syndrome, which may be used additionally for early identification of high-risk subjects.