tbuckley/cabot-search huggingface dataset:
Characterizing the clinical relevance of digital phenotyping data quality with applications to a cohort with schizophrenia
Authors: John Torous, Patrick Staples, Ian Barnett, Luis R. Sandoval, Matcheri Keshavan, Jukka-Pekka Onnela
Journal: npj Digital Medicine (2018)

Digital phenotyping, or the moment-by-moment quantification of the individual-level human phenotype in situ using data from personal digital devices and smartphones, in particular, holds great potential for behavioral monitoring of patients. However, realizing the potential of digital phenotyping requires understanding of the smartphone as a scientific data collection tool. In this pilot study, we detail a procedure for estimating data quality for phone sensor samples and model the relationship between data quality and future symptom-related survey responses in a cohort with schizophrenia. We find that measures of empirical coverage of collected accelerometer and GPS data, as well as survey timing and survey completion metrics, are significantly associated with future survey scores for a variety of symptom domains. We also find evidence that specific measures of data quality are indicative of domain-specific future survey outcomes. These results suggest that for smartphone-based digital phenotyping, metadata is not independent of patient-reported survey scores, and is therefore potentially useful in predicting future clinical outcomes. This work raises important questions and considerations for future studies; we explore and discuss some of these implications.
Improved Patency of ePTFE Grafts as a Hemodialysis Access Site by Seeding Autologous Endothelial Cells Expressing Fibulin-5 and VEGF
Authors: Itai Tzchori, Mizied Falah, Denis Shteynberg, Dana Levin Ashkenazi, Zeev Loberman, Luba Perry, Moshe Y. Flugelman
Journal: Molecular Therapy (2018)

Small caliber synthetic vascular grafts used for dialysis access sites have high failure rates due to neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. We tested the use of ePTFE grafts seeded with autologous ECs expressing fibulin-5 and vascular endothelial growth factor (VEGF), as a dialysis access site in a porcine model. We connected the carotid arteries and jugular veins of 12 miniature pigs using 7-mm ePTFE grafts; five grafts were seeded with autologous venous ECs modified to express fibulin-5 and VEGF, and seven unseeded grafts were implanted at the same location and served as controls. At 6 months, after completion of angiography, the carotid arteries and jugular veins with the connecting grafts were excised and fixed. Autologous EC isolation and transduction and graft seeding were successful in all animals. At 3 months, 4 of 5 seeded grafts and 3 of 7 control grafts were patent. At 6 months, 4 of 5 (80%) seeded grafts and only 2 of 7 (29%) control grafts were patent. Seeding ePTFE vascular grafts with genetically modified ECs improved long term small caliber graft patency. The biosynthetic grafts offer a novel therapeutic modality for vascular access in hemodialysis. Small caliber synthetic vascular grafts used for dialysis access sites have high failure rates due to neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. We tested the use of ePTFE grafts seeded with autologous ECs expressing fibulin-5 and vascular endothelial growth factor (VEGF), as a dialysis access site in a porcine model. We connected the carotid arteries and jugular veins of 12 miniature pigs using 7-mm ePTFE grafts; five grafts were seeded with autologous venous ECs modified to express fibulin-5 and VEGF, and seven unseeded grafts were implanted at the same location and served as controls. At 6 months, after completion of angiography, the carotid arteries and jugular veins with the connecting grafts were excised and fixed. Autologous EC isolation and transduction and graft seeding were successful in all animals. At 3 months, 4 of 5 seeded grafts and 3 of 7 control grafts were patent. At 6 months, 4 of 5 (80%) seeded grafts and only 2 of 7 (29%) control grafts were patent. Seeding ePTFE vascular grafts with genetically modified ECs improved long term small caliber graft patency. The biosynthetic grafts offer a novel therapeutic modality for vascular access in hemodialysis.
Validation of a multi-marker panel for early detection of ovarian cancer.
Authors: Robert C. Bast, Archana Raamanathan, Aleksandra Gentry-Maharaj, Steven Skates, Keith A. Baggerly, Rania Fourkala, Andy Ryan, Zhen Zhang, Usha Menon, Ian Jacobs
Journal: Journal of Clinical Oncology (2016)

5570 Background: Ovarian cancer is a high mortality gynecological malignancy with poor survival rates, where patients might benefit from early stage detection strategies. The United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) study employed a multi-modal screening (MMS) strategy utilizing longitudinal CA125 values interpreted with a risk of ovarian cancer algorithm (ROCA) as a first line screen to triage women for confirmatory transvaginal ultrasound. MMS achieved a sensitivity of 84% for invasive epithelial ovarian/tubal cancer (iEOC) diagnosed within 1 year of screens. Despite the promise of this strategy, about 15-20% of iEOC do not express CA125 and will be missed. We previously identified a panel of biomarkers comprising CA125, HE4, MMP-7 and CA 72-4 that could distinguish early stage ovarian cancers from healthy individuals with 83% sensitivity at 98% specificity. Methods: In this work, we retrospectively assessed pre-clinical longitudinal specimens from 75 women destined to develop ovarian cancer (3-5 serial specimens each) and 525 corresponding controls (5 serial specimens each) from the UKCTOCS study, in a blinded trial, to estimate complementarity and lead times for the biomarker panel in comparison to CA125. Of the 75 cases, 50 were CA125 screen positive and 25 were CA125 screen negative. We developed flow cytometric bead-based immunoassays for the biomarker panel with low %CVs and limits of detection suitable for assessment of low biomarker concentrations to permit assessment using ultra-low (16 µL) volumes of serum. Results: One or more markers rose with CA125 in the screen positive samples, however, no lead times were observed. We developed single marker longitudinal algorithms to determine the presence of a change point to distinguish between the cases and controls, similar in principle to the ROCA algorithm. Based on this algorithm, HE4 and CA72-4 identified 16% of cases missed by CA125 at 98% specificity. MMP-7 did not identify any cases missed by CA125. Conclusions: HE4 and CA72-4 show promise to complement CA125 in a longitudinal screening strategy.
HypAir <i>F</i><sub>eNO</sub>: an electrochemical sensor
Authors: Cristina Ramos Hernández, Marta Núñez Fernández, Cecilia Mouronte-Roibas, Mar Mosteiro Añon, Alberto Fernández-Villar
Journal: European Respiratory Journal (2018)

We would like to congratulate Alcázar-Navarrete et al. [1] on their paper which was published in a recent issue of the European Respiratory Journal . The authors observed that persistent exhaled nitric oxide fraction ( F eNO) values ≥20 ppb in clinically stable chronic obstructive pulmonary disease (COPD) outpatients are associated with a significantly higher risk of acute exacerbations of COPD (AECOPD). This kind of approach would certainly have significant consequences for the follow-up of COPD patients. HypAir FeNO is an electrochemical sensor; there is no chemiluminescence NO device <http://ow.ly/tmvX30irOO7>
Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita
Authors: Martin Kirschner, Angela Maurer, Marcin W. Wlodarski, Monica S. Ventura Ferreira, Anne-Sophie Bouillon, Insa Halfmeyer, Wolfgang Blau, Michael Kreuter, Martin Rosewich, Selim Corbacioglu, Joachim Beck, Michaela Schwarz, Jörg Bittenbring, Markus P. Radsak, Christian Matthias Wilk, Steffen Koschmieder, Matthias Begemann, Ingo Kurth, Mirle Schemionek, Tim H. Brümmendorf, Fabian Beier
Journal: Leukemia (2018)
Abstract #399: The antidepressants fluoxetine and maprotiline induce apoptosis and type-II autophagic-programmed cell death in Burkitt\#8217;s lymphoma in vitro independently of SERT and NET
Authors: Suzanne Cloonan, D. Clive Williams
Journal: Cancer Research (2009)

We report for the first time that the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the noradrenaline transporter (NET)-selective inhibitor (NSRI) maprotiline induce type-II autophagic-programmed cell death (PCD) in the malignancy Burkitt\#8217;s lymphoma (BL). SERT has been shown to be expressed in BL and has been suggested as a novel pro-apoptotic target for SERT targeting agents. We have previously shown that the SERT ligands serotonin, fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA or \#8216;Ecstasy\#8217;) have no significant apoptotic effect in a range of BL cell lines despite some of these cell lines expressing SERT. Fluoxetine and maprotiline were found to induce time and dose-dependent apoptosis in a range of malignancies including BL within rational  in vivo  pharmacological doses. These monoamine transporter ligands have the ability to induce programmed cell death (PCD) in BL independently of SERT and NET despite the expression of these transporters on some of these BL cell lines. In this study it was found that both maprotiline and fluoxetine induce type I programmed cell death (apoptosis) in biopsy-like BL cells (MUTU-I c179) as shown by PARP cleavage, DNA fragmentation and caspase-dependent involvement. Maprotiline and fluoxetine induce an alternative form of programmed cell death (PCD) in the highly resistant BL cell line DG-75, a type of cell death that does not involve caspases, DNA fragmentation or PARP cleavage and is associated with the development of cytoplasmic vacuoles consistent with type-II or an autophagic mode of PCD. This was confirmed by transmission electron microscopy, up-regulation of the autophagic specific gene Beclin-I and the extent of PCD being reduced by the autophagic inhibitor 3-MA.   It appears that calcium signalling plays a role in the response of both cell lines to fluoxetine and maprotiline, with extracellular and intracellular Ca 2+  being important for DG-75 and MUTU-I cells respectively. Maprotiline- and fluoxetine -induced cell death in both cell lines was insensitive to the anti-oxidant N-acetyl-cysteine consistent with reactive oxygen species having no role in this process. The response of both cell lines to maprotiline and fluoxetine was affected by serine protease inhibitors implicating a role for such modulators in the mechanism of cell death induced by these monoamine transporter ligands. In the present study we establish important features that single out the cell death mechanisms induced by maprotiline and fluoxetine in two Burkitt\#8217;s lymphoma cell lines, particularly the ability of these ligands to induce type-II autophagic-PCD in resistant BL cells, which may suggest an alternative therapeutic application for these compounds.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 399.
EGFR-TKIs resistance via EGFR-independent signaling pathways
Authors: Qian Liu, Shengnan Yu, Weiheng Zhao, Shuang Qin, Qian Chu, Kongming Wu
Journal: Molecular Cancer (2018)

Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.
New Methods for Inferring the Distribution of Fitness Effects for INDELs and SNPs
Authors: Henry J Barton, Kai Zeng
Journal: Molecular Biology and Evolution (2018)

Small insertions and deletions (INDELs; ≤50 bp) are the most common type of variability after single nucleotide polymorphism (SNP). However, compared with SNPs, we know little about the distribution of fitness effects (DFE) of new INDEL mutations and how prevalent adaptive INDEL substitutions are. Studying INDELs has been difficult partly because identifying ancestral states at these sites is error-prone and misidentification can lead to severely biased estimates of the strength of selection. To solve these problems, we develop new maximum likelihood methods, which use polymorphism data to simultaneously estimate the DFE, the mutation rate, and the misidentification rate. These methods are applicable to both INDELs and SNPs. Simulations show that they can provide highly accurate results. We applied the methods to an INDEL polymorphism data set in Drosophila melanogaster. We found that the DFE for polymorphic INDELs in protein-coding regions is bimodal, with the variants being either nearly neutral or strongly deleterious. Based on the DFE, we estimated that 71.5–83.7% of the INDEL substitutions that took place along the D. melanogaster lineage were fixed by positive selection, which is comparable with the prevalence of adaptive substitutions at nonsynonymous sites. The new methods have been implemented in the software package anavar.
Keeping athletes on the field: preventing primary and secondary ACL injuries
Authors: Amelia J.H. Arundale
Journal: British Journal of Sports Medicine (2018)

I aimed to (1) examine the changes in biomechanics and injury incidence with utilisation of the 11+ prevention programme over two soccer seasons in collegiate women, (2) establish the incidence of lower extremity injuries and career duration after ACL reconstruction (ACLR) and return Major League Soccer (MLS) and (3) quantify the effects of a secondary injury prevention programme on function, return to sport, and second ACL injury incidence in athletes after ACLR.

Due to the high incidence of ACL injuries in cutting, pivoting and jumping sports, it would change athletes’ lives if it were possible to prevent a first or a second ACL injury.1 Primary and secondary ACL injury prevention programmes have been developed but require outcomes testing to determine their efficacy and further improve their impact.

### Aim 1

Two collegiate women’s soccer teams performed the 11+ prevention programme2 for two seasons, while a control team performed their normal …
Abstract P073: Diabetes and All Cause and Cause-specific Mortality in 111,300 Mexican Women With Healthcare Coverage
Authors: Susana Lozano-Esparza, Ruy Lopez-Ridaura, Eduardo Ortiz-Panozo, Clicerio González-Villalpando, Carlos Aguilar-Salina, Juan Eugenio Hernández-Ávila, Mauricio Hernández-Ávila, Martín Lajous
Journal: Circulation (2018)

Introduction: In high-income countries, mortality rates have a twofold increment in subjects with diabetes compared to the general population. Few prospective studies have evaluated the impact of diabetes on mortality in low- and middle-income countries. In Mexico, a five-fold higher mortality due to diabetes was recently reported. Limited access to medical care could explain this poor prognosis. Hypothesis: Among women with healthcare coverage in Mexico, diabetes confers a mortality risk similar to what is observed in high-income countries. Methods: We evaluated diabetes in relation to all cause and cause-specific mortality in a prospective cohort of 111,300 disease-free women (except for diabetes) with healthcare coverage in the Mexican Teachers’ Cohort. We identified 5,514 (5%) participants who self-reported a diagnosis of diabetes at baseline in 2006-08. Between 2006 and 2015 we identified deaths using the employer’s database and next of kin reports and obtained date and cause of death of 802 women from national mortality databases. In multivariable Cox models we adjusted for sociodemographic factors, healthcare institution, use of preventive health services, body mass index, hypertension, smoking, and physical activity. Results: Among participants (42 ± 7.5 years), age-adjusted mortality rate was 4.59 per 1000 person-years (95%CI 3.27, 5.92) for women with diabetes and 1.28 per 1000 person-years (95%CI 1.01, 1.54) for women without diabetes. In multivariable models comparing diabetics versus non diabetics, the hazard ratio (HR) for all-cause mortality was 3.27 (95%CI 2.73, 3.90). The HR for cardiovascular mortality was 3.78 (95%CI 2.46, 5.54), for renal disease mortality 16.89 (95%CI 9.78, 29.4), and for death from infections 7.55 (95%CI 3.58, 15.3). Conclusions: In women with healthcare coverage in Mexico, diabetes was associated with a worse prognosis than what is observed in high-income countries, particularly for deaths due to renal disease and infections.
Nasal hyperreactivity in rhinitis: A diagnostic and therapeutic challenge
Authors: L. Van Gerven, B. Steelant, P. W. Hellings
Journal: Allergy (2018)

Although nasal hyperreactivity (NHR) is a common feature in patients suffering from allergic and nonallergic rhinitis, it is widely neglected during history taking, underdiagnosed in the majority of patients with rhinitis and rhinosinusitis, not considered as an outcome parameter in clinical trials on novel treatments for rhinitis and rhinosinusitis, and no target for routine treatment. In contrast to the simple nature of diagnosing NHR by a history of nasal symptoms induced by nonspecific exogenous and/or endogenous triggers, quantification is hardly performed in routine clinic given the lack of a simple tool for its diagnosis. So far, limited efforts have been invested into gaining better insight in the underlying pathophysiology of NHR, helping us to explain why some patients with inflammation develop NHR and others not. Of note, environmental and microbial factors have been reported to influence NHR, contributing to the complex nature of understanding the development of NHR. As a consequence of the neglect of NHR as a key clinical feature of rhinitis and chronic rhinosinusitis (CRS), patients with NHR might be suboptimally controlled and/or dissatisfied with current treatment. We here aim to provide a comprehensive overview of current knowledge on the pathophysiology, and the available tools to diagnose and treat NHR.
Prognostic and predictive factors in metastasic colorectal cancer.
Authors: Pilar Garcia Alfonso, Gonzalo Garcia, Iria Gallego, Isabel Peligros, Ana Corcuera, Beatriz Puente, Miriam Lobo De Mena, Ana Ruperez, Gema Aguado, Carmen Sandoval, Montserrat Blanco-Codesido, Aitana Calvo, Andres J. Muñoz Martín, Miguel Martin
Journal: Journal of Clinical Oncology (2018)

690 Background: In recent years, prognostic and predictive factors in mCRC are becoming more important, outstanding the tumor and metastasic location, the primary tumor and/or metastasis resections as well as molecular biomarkers (KRAS, NRAS, BRAF and PIK3CA). Methods: We conducted a retrospective study of 334 patients with mCRC diagnosticated between January 2010 and June 2015 in the Oncology Service from HGUGM. The objective of our study was to evaluate the overall survival (OS) relating to each of these settings. We also evaluated OS considering the biological treatment received in first line. Multivariant analysis was performed with independence of tumor and metastasic location, metastasectomies, no primary tumor resection, biological treatment used in first line, age, sex and moleculars biomarkers. Results: Median OS was 24,34m. The advantageous prognostic factors which statistically significant impact on the median OS have been triple (RAS and BRAF) (n = 86) and quadruple (RAS, BRAF and PIK3CA) (n = 76) wild-type (wt 36,6m vs mut 23m, p = 0,02; wt 37,6m vs mut 23,38m, p = 0.02, respectively), left tumor location with rectum (left 25,55m vs right 19,44m, p = 0,001) and isolated hepatic and pulmonary metastasic location (30,32 vs 23 m, p = 0,03; 45,32m vs 23,38 m, p = 0,004, respectively). The main disadvantageous prognostic factor has been the no primary tumor resection (13,75m vs 31,61m, p = 0,00001) with independence of synchronous presentation of the disease as well as biomarkers mutational status. Median OS in first line was 30.13 m with bevacizumab (n = 54) vs 16,18m with antiEGFR (n = 28) (p = 0.02) in extended RAS wild-type patients (n = 101). Considering the multivariate analysis, the independent prognostic factors have been the isolated pulmonary metastasis (HR = 0,46; CI 95% 0,30-0,73;p = 0,001), quadruple wild-type (HR = 0,69;CI 95% 0,49-0,97; p = 0,031), metastasectomies (HR = 0,29; CI 95% 0,21-0,4; p = 0,000), right location (HR = 1,43; CI 95% 1,08-1,9;p = 0,014) and no primary tumor resection (HR = 2,06; CI 95% 1,49-2,86; p = 0,000). Conclusions: Isolated pulmonary metastasis, quadruple wild-type, metastasectomies, left location and primary tumor resection have independent positive prognostic value, according to our retrospective study.
Letter by Jin-shan and Xue-bin Regarding Article, “Worsening Conduction Delay in Hypertrophic Cardiomyopathy: What Drug Is Responsible?”
Authors: He Jin-shan, Li Xue-bin
Journal: Circulation (2018)

We read with great interest the case presented by García-Granja and colleagues 1 about worsening conduction delay in hypertrophic cardiomyopathy when taking propafenone for atrial fibrillation.We have 3 questions about this interesting case.First, baseline ECG shows first atrioventricular block with PR interval 0.280 seconds long, a nonspecific conduction delay with QRS complex 0.110 seconds wide, an R wave absent on leads V1 and V2, and asymmetrical and negative T waves in lateral leads (V3-V6, I, and aVL).All these ECG changes indicate that there is structural abnormality with this patient, proved by cardiac magnetic resonance.Conduction delay in the atrialventricular node and ventricle are preexisting.Will this make the patient prone to proarrhythmic effects of antiarrhythmic drugs?Is this the real reason for propafenone's obvious exacerbation of conduction delay?Second, this patient is diagnosed with paroxysmal atrial fibrillation with palpitations, and antiarrhythmic drugs show obvious side effects on him.Can we try to treat the atrial fibrillation by catheter ablation?Third, although it is the patient's first episode of atrial fibrillation, cardiac magnetic resonance confirms the diagnosis of hypertrophic cardiomyopathy, which has a high risk of thromboembolism.Do we need to prescribe anticoagulants for this patient now?