tbuckley/cabot-search huggingface dataset:
Cost Sharing and Mental Health Care
Authors: Benjamin G. Druss
Journal: JAMA Psychiatry (2017)

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Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications
Authors: Benjamin Kasenda, Stefan Schandelmaier, Xin Sun, Erik von Elm, John You, Anette Blümle, Yuki Tomonaga, Ramon Saccilotto, Alain Amstutz, Theresa Bengough, Joerg J Meerpohl, Mihaela Stegert, Kelechi K Olu, Kari A O Tikkinen, Ignacio Neumann, Alonso Carrasco-Labra, Markus Faulhaber, Sohail M Mulla, Dominik Mertz, Elie A Akl, Dirk Bassler, Jason W Busse, Ignacio Ferreira-González, Francois Lamontagne, Alain Nordmann, Viktoria Gloy, Heike Raatz, Lorenzo Moja, Rachel Rosenthal, Shanil Ebrahim, Per O Vandvik, Bradley C Johnston, Martin A Walter, Bernard Burnand, Matthias Schwenkglenks, Lars G Hemkens, Heiner C Bucher, Gordon H Guyatt, Matthias Briel
Journal: BMJ (2014)
Reductions in urinary mutagenicity after switching from a conventional cigarette to electrically heated cigarette smoking systems
Authors: Claire Martin Leroy, Dirk Lindner, Anthony R. Tricker
Journal: Cancer Research (2006)

464   The aim of this study was to investigate the effect of switching from a conventional cigarette to electrically heated cigarette smoking systems (EHCSS) on the excretion of mutagenic material in urine (‘urinary mutagenicity’). Adult Caucasian smokers (80 male and 80 female; 10-25 cigarettes per day) of Marlboro Lights (ML6: 6mg ISO ‘tar’) were randomized to 5 study groups (N=32/group): continue smoking ML6, switch to smoking EHCSS of either 5mg (EHCSS-K6) or 3mg (EHCSS-K3) ISO ‘tar’ delivery, the Philip Morris 1 cigarette (PM1: 1mg ISO ‘tar’), or no-smoking (NS). The study was composed of a baseline phase where all smokers smoked ML6 (Days -1, 0) and a study phase (Days 1-8) where smoking was according to randomized study group. Smoking was controlled and all subjects consumed an identical low-mutagen diet in both phases. Excretion of mutagenic material in 24h urine samples was determined on Days 0, 5, and 8 using the Ames plate incorporation assay with  Salmonella typhimurium  strain YG1024 in the presence of a metabolic activation system (S9). Tester strain YG1024 is an  O -acetyltransferase-overproducing derivative of strain TA98, and is highly sensitive to the mutagenic activity of aromatic nitro, heterocyclic aromatic amines and hydroxylamino compounds. Other biomarkers analyzed in the study included blood carboxyhemoglobin, serum cotinine, and excretion of nicotine equivalents in urine. Conduct of the study and urine analysis were performed by an independent contract research organization in accordance with Good Clinical Practice and Good Laboratory Practice. Following concentration and extraction of 464 urine samples on XAD2 resin and reconstitution in DMSO, 49 urine sample extracts (10.6%) with evidence of precipitate and/or cytotoxicity were classified as non assessable and were excluded from analysis. Average cigarette consumption (cigarettes per day: CPD) was similar in all smoking groups and study days. On Day 0, excretion of mutagenic material in urine expressed as revertants/24h (mean ± SD) was higher in males (43,524 ± 20,047) compared to females (30,450 ± 14,037),  p  p =0.0010. No significant difference in the excretion of mutagenic material in urine was observed in smokers who continued to smoke ML6 from Day 0 compared to Day 8 (38,449 ± 16,626  vs . 41,873 ± 21,804;  p =NS). Statistically significant reductions ( p  vs . Day 8) from ML6 to either EHCSS-K6 (37,176 ± 23,884  vs . 11,624 ± 10,719; -67.8%) or EHCSS-K3 (38,699 ± 18,311  vs . 14,123 ± 11,213; -66.9%), PM1 (35,568 ± 17,447  vs . 22,384 ± 13,582; -33.9%), or to NS (36,228 ± 16,848  vs . 6,131 ± 6,121; -81.9%).
Evidence for Genetic Risk Contributing to Long-Term Adverse Treatment Effects in Childhood Cancer Survivors
Authors: Maria Monica Gramatges, Smita Bhatia
Journal: Annual Review of Medicine (2017)

Survivors of childhood cancer are at increased risk for therapy-related morbidities and mortality. Although the demographic and clinical factors predicting the risk for long-term effects of cancer therapy are well known, the impact of genetic risk for specific late effects is less clearly defined. Here, we review the extant literature and recent research describing genetic modifiers to risk for the more common late effects of childhood cancer therapy. Results of this research support the need for clinical trials that attempt to further refine risk prediction by incorporating genetic testing into existing algorithms that are primarily based on clinical and demographic factors. Confirmation of genetic predisposition, as defined by reproducibility and prospective validation, would permit therapeutic modification and discussion of individualized survivor care plans even at initial cancer diagnosis.
Abstract 222: CCN5 Overexpression Triggers Early Amplification Followed by Regression of Electrical Remodeling in a Pressure Overload Rat Model
Authors: Jun Hu, Dongtak Jeong, Antoine H Chaanine, Lukas J Motloch, Chaoqin Xie, Roger J Hajjar, Fadi G Akar
Journal: Circulation Research (2015)

The matricellular proteins CCN2 &amp; CCN5 play opposing roles in pressure overload hypertrophy (PoH). While CCN2 promotes adverse remodeling, CCN5 suppresses fibrosis and therefore may be an important therapeutic target. Since arrhythmias are prevalent during early stages of PoH, we investigated the electrophysiological (EP) effects of CCN5 gene transfer (GT) in a rat model. We hypothesized that CCN5 GT prevents electromechanical dysfunction in PoH. Methods: 4 wk old rats underwent aortic constriction and were randomized to receive AAV9 CCN5 or an empty vector (E) 3 wks later. In vivo hemodynamic analysis followed by ex vivo EP measurements using high resolution optical action potential (AP) mapping were performed at 9 or 21 wks of PoH. Results: CCN5 GT did not prevent but rather amplified early electromechanical remodeling as fractional shortening was significantly reduced, AP duration prolonged, and conduction velocity (CV) impaired in AAV9 CCN5 compared to AAV9 E hearts (Fig, top). Remarkably EP remodeling in AAV9 CCN5 hearts was largely reversed by 21 wks of PoH (Fig, top). To probe the basis of these unexpected findings, we tested whether CCN5 GT alters the EP substrate in normal (fibrosis free) hearts. Indeed AAV9 CCN5 GT caused significant CV slowing, consistent with a potent effect on excitability that was independent of fibrosis (Fig, bottom). Conclusions: CCN5 GT alters myocardial conduction by directly modulating gap junction and/or Na channel function. EP remodeling is amplified during early PoH but undergoes regression at later stages possibly through reversal of fibrosis. CCN5 modulates the EP substrate via fibrosis dependent (late) and independent (early) effects.
Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction
Authors: Susanna C. Larsson, Stephen Burgess, Karl Michaëlsson
Journal: JAMA (2017)

Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.Genetic risk score based on genetic variants related to elevated serum calcium levels.Co-primary outcomes were the odds of CAD and myocardial infarction.Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
The T-cell leukemia-associated ribosomal RPL10 R98S mutation enhances JAK-STAT signaling
Authors: T Girardi, S Vereecke, S O Sulima, Y Khan, L Fancello, J W Briggs, C Schwab, J Op de Beeck, J Verbeeck, J Royaert, E Geerdens, C Vicente, S Bornschein, C J Harrison, J P Meijerink, J Cools, J D Dinman, K R Kampen, K De Keersmaecker
Journal: Leukemia (2017)
Calcium Signaling and Cytotoxicity
Authors: George E. N. Kass, Sten Orrenius
Journal: Environmental Health Perspectives (1999)

The divalent calcium cation Ca2+ is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype.The basis to the signaling role of Ca2+ is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca2+ in the cytosol of the cell (lCa2+1) but that are also coupled to major dynamic and rapidly exchanging stores.This enables extracellular signals from hormones and growth factors to be transduced as ICa2+li spikes that are amplitude and frequency encoded.There is considerable evidence that a number of toxic environmental chemicals target these Ca2+ signaling processes, alter them, and induce cell death by apoptosis.Two major pathways for apoptosis will be considered.The first one involves Ca2+-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1).In the second pathway, Ca2+ has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER).Mitochondria may respond to an apoptotic Ca2+ signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore.Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca2+ stores, will induce as a direct result of this effect the opening of plasma membrane Ca2+ channels and an ER stress response.In contrast, under some conditions, Ca2+ signals may be cytoprotective and antagonize the apoptotic machinery.
Efficacy and safety of checkpoint blockade for treatment of advanced melanoma (mel) in patients (pts) age 80 and older (80+).
Authors: Claire Frances Friedman, Troy Z Horvat, Janna Minehart, Katherine Panageas, Margaret K. Callahan, Paul B. Chapman, Parisa Momtaz, Michael Andrew Postow, Alexander Noor Shoushtari, Jedd D. Wolchok, Stuart M. Lichtman
Journal: Journal of Clinical Oncology (2016)

10009 Background: Little is known about the use of checkpoint blockade in pts aged 80+. Here we report the efficacy and safety of these agents in this pt population. Methods: We identified mel pts at MSKCC aged 80+ who received at least 1 dose of ipilimumab (ipi), pembrolizumab or nivolumab (anti-PD1) or the combination of ipi+nivo and had a least 1 follow-up visit. 7 pts received anti-PD1 after ipi at MSKCC. Adverse events (AEs) graded using CTCAE v4.0 were collected. Pts who received anti-PD1 were grouped. Pts who received ipi and then anti-PD1 at MSKCC had AEs collected for both drugs but were included in the ipi survival analysis. Results: The rate of AEs was similar across groups, but the rate of grade ≥ 3 events was higher in the ipi+nivo group. There were no treatment-related deaths. 5/74 (6.8%) ipi pts, 0/24 anti-PD1 pts and 3/8 (37.5%) ipi+nivo pts required infliximab for diarrhea. An asymptomatic increase in lipase was seen in 4/8 (50%) ipi+nivo pts and 2/24 (8.3%) of anti-PD1 pts. Fatigue occurred in 4/8 (50%) of ipi+nivo pts and 6/24 (25%) of anti-PD1 pts. In the anti-PD1 group, there was one case each of grade 4 anemia and nausea/vomiting. Median overall survival (OS) was 7.5 months (95% CI: 6.0, 13.7) in the ipi pts, 14.2 months (95% CI: 5.3, not reached (NR)) in the anti-PD1 pts and 23.5 months (95% CI: 1.5, NR) in the ipi+nivo pts. Conclusions: The rate of AEs in pts aged 80+ is comparable to published phase III data in all age groups. PD-1 inhibitors and ipi+nivo prolong survival compared to ipi alone in this age group. Further study of these agents in this age group is needed. Ipi (N = 74) Anti-PD1 (N = 24) Nivo+Ipi (N = 8) Age - yr Mean, range 84, (80-93) 86, (80-94) 82, (80-87) Sex -no. (%) Male 55(74.3) 16(66.7) 2 (25) Female 19(25.7) 8 (33.3) 6 (75) Toxicity Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 All AEs 65(87.8) 22(29.7) 21(87.5) 5(20.8) 7(87.5) 5(62.5) Diarrhea 32(43.2) 13(17.6) 2(8.3) 1(4.2) 5(62.5) 2(25) Transaminitis 41(55.4) 10(13.5) 0(0) 0(0) 6(75) 2(25) Pruritus 0(0) 0(0) 7(29.2) 0(0) 3(37.5) 0(0) Rash 28(37.8) 4(5.4) 8(33.3) 0(0) 5(62.5) 1(12.5) Pneumonitis 0(0) 0(0) 2(8.3) 0(0) 2(25) 0(0) Arthralgia/Myalgia 0(0) 0(0) 4(16.7) 0(0) 1(12.5) 0(0) Hypophysitis 4(5.4) 2(2.7) 0(0) 0(0) 0(0) 0(0)
PNPLA3/adiponutrin genotype is strongly associated with metabolic syndrome components and liver damage in patients with Nonalcoholic Fatty Liver Disease
Authors: L. Valenti, E. Galmozzi, P. Dongiovanni, R. Rametta, E. Lattuada, M. Zappa, E. Mozzi, G. Roviaro, M. Maggioni, Ester Vanni, Elisabetta Bugianesi, A. L. Fracanzani, S. Fargion
Journal: Hepatology (2009)
Abstract 403: Mitochondrial Complex II is a Source of the Reserve Respiratory Capacity that is Regulated by Metabolic Sensors via Sirtuin 3
Authors: Jessica Pfleger, Minzhen He, Maha Abdellatif
Journal: Circulation Research (2015)

A cell’s survivability depends on its ability to meet its energy requirements. We hypothesized that the cells’ mitochondrial reserve respiratory capacity (RRC) is a critical component of its bioenergetics that can be utilized during an increase in energy demand, thereby, enhancing viability. Our goal was to identify the elements that regulate and contribute to the development of RRC and its involvement in cell survival. Our results show that development of RRC is dependent on metabolic substrate availability in a cell type-dependent manner. While the neonatal rat cardiac myocytes (NRCM) utilize glucose as the main substrate, developing a RRC [1.4-2.5 fold higher than basal oxygen consumption rate (OCR)] required fatty acids in addition to glucose. Accordingly, inhibition of either glucose or fatty acid oxidation separately, completely abrogated RRC, while having little impact on basal OCR, which is sustainable with either substrate or glutamate in the medium. Conversely, RRC was enhanced (1.4-1.8 fold) through increasing glucose oxidation via inhibiting pyruvate dehydrogenase kinase with dichloroacetate, or through increasing fatty acid oxidation via activation of AMP-activated kinase (AMPK). The latter was partly mediated through peroxisome proliferator-activated receptor alpha. These results suggested that RRC is an independently regulated entity of the cells’ bioenergetics. An electron flow activity assay revealed that the increase in RRC correlated with a specific increase in complex II (cII) activity. Inhibiting or disassembling holo cII completely abolished RRC, accompanied by a slight decrease in basal OCR (0.82-0.9 fold), thus confirming it as the source of RRC. Moreover, the development of RRC required Sirtuin (Sirt)3. Functionally, we show that enhancing RRC via fatty acid oxidation with 5-Aminoimidazole-4-carboxamide 1-β-Dribofuranoside in NRCM results in a burst of cII-dependent oxidative phosphorylation accompanied by reduced superoxide production and enhanced cell survival post-energy deprivation conditions. Thus, for the first time, we show that metabolic sensors increase the cells’ RRC via activating cII in a Sirt3-dependent manner, and that this mechanism can be exploited for increasing cell survival after hypoxia.
Exceptionalism in HIV
Authors: P. Godfrey-Faussett, R. Baggaley, M F Brewster
Journal: BMJ (1998)

# Challenge for Africa too {#article-title-2}

EDITOR—The 24 January issue on antenatal HIV testing emphasised the need to promote routine voluntary HIV counselling and testing to maximise the opportunity for interventions in those found to be infected. More than 20 million of the 30 million people estimated to be infected with HIV at the end of 1997 live in sub-Saharan Africa, where some spend less than $15 (£9) per capita on health each year and over 90% of those infected are unaware of their infection. The opportunities for the medical interventions discussed are therefore limited.

Nevertheless, although individual benefits may be small, the potential benefits for society are huge. HIV/AIDS “exceptionalism” in parts of Africa has led to an environment of stigma and denial, with the tacit support of policy makers and healthcare staff. HIV is rarely entered in African death certificates, yet treatment decisions are made on the assumption that a patient is infected. Half of those counselling others to consider HIV testing …
Cost-Effectiveness Analysis of Afatinib versus Gefitinib for First-Line Treatment of Advanced EGFR -Mutated Advanced Non–Small Cell Lung Cancers
Authors: Christos Chouaid, Laura Luciani, Katell LeLay, Pascal Do, Jaafar Bennouna, Maurice Perol, Denis Moro-Sibilot, Alain Vergnenègre, Gérard de Pouvourville
Journal: Journal of Thoracic Oncology (2017)

The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation-positive NSCLCs. Afatinib and gefitinib costs and patients' outcomes in France were assessed.A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation-positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were conducted.For all EGFR mutation-positive NSCLCs, the afatinib-versus-gefitinib ICER of was €45,211 per quality-adjusted life-year (QALY) (0.170 QALY gain for an incremental cost of €7697). ICERs for EGFR exon 19 deletion and L858R populations were €38,970 and €52,518, respectively. Afatinib had 100% probability to be cost-effective at a willingness-to-pay threshold of €70,000/QALY for patients with common EGFR mutations.First-line afatinib appears cost-effective compared with gefitinib for patients with EGFR mutation-positive NSCLCs.