tbuckley/cabot-search huggingface dataset:
Abstract P211: A Method to Impute Life-course Trajectories of Cardiovascular Risk Factors from Pooled Cohorts Data
Authors: Yiyi Zhang, Eric Vittinghoff, Mark J Pletcher, Norrina B Allen, Adina Zeki Al Hazzouri, Kristine Yaffe, Pallavi B Balte, Alvaro Alonso, Anne B Newman, Diane G Ives, Jamal S Rana, Donald Lloyd-Jones, Ramachandran S Vasan, Elizabeth C Oelsner, Andrew E Moran
Journal: Circulation (2018)

Introduction: Cumulative exposure to cardiovascular disease (CVD) risk factors during young adulthood is associated with later life CVD risk. Few prospective cohort studies measured exposures in young adulthood. We sought to develop and validate a method to impute trajectories of CVD risk factors across the life course. Methods: 36,546 participants (55% women, 25% black, average exams 5.1/participant) from 6 studies (ARIC, CARDIA, CHS, Framingham Offspring, Health ABC, and MESA) were included. Demographics and CVD risk factors (BMI, smoking, BP, lipids, glucose, medications for BP, lipids and glucose) were collected at each exam and harmonized across cohorts. We multiply imputed complete risk factor trajectories from age 18 to 99 years for each participant using an extension of linear mixed modeling (for continuous variables) and interval-censored survival modeling (for categorical variables), taking into account the multilevel structure of data. For validation, we randomly selected 25% of all participants and deleted their observed data for exam age 20-35, 50-65, or 80-95 years. We then imputed risk factor values for deleted age periods and compared imputed values with directly observed values. Results: Imputed values were relatively consistent with observed values for BMI, SBP, LDL, and glucose, particularly in young and middle ages ( Figure ). The mean (standard deviation) of the difference between imputed vs. observed values for BMI, SBP, LDL, and glucose were 0.1 (2.7) kg/m 2 , 0.9 (16.3) mm Hg, -1.1 (30.2) mg/dL, and -0.6 (23.0) mg/dL. The prevalence of imputed smoking, diabetes, and medications were also consistent with observed data. Conclusions: We demonstrated a validated method for estimating CVD risk factor trajectories across the life course. This approach may advance understanding of potential impact of cumulative early risk factor exposures on later life CVD risk, and inform primary prevention strategies over the life course. Figure. Mean and prevalence of observed vs. imputed risk factors by age periods 2
Correlation of In Vivo [<sup>18</sup>F]Flortaucipir With Postmortem Alzheimer Disease Tau Pathology
Authors: Ruben Smith, Moa Wibom, Daria Pawlik, Elisabet Englund, Oskar Hansson
Journal: JAMA Neurology (2018)

<h3>Importance</h3> In Alzheimer disease (AD), tau filaments form neuronal inclusions in neurites (neuropil threads) and in somata (neurofibrillary tangles), and neurite tau pathology constitutes the most common pathology. Positron emission tomography (PET) ligands have been developed to detect in vivo tau pathology in AD. However, the association of AD tau pathology post mortem with in vivo tau PET retention has not been established. Therefore, there is a need to investigate the associations of tau PET with postmortem tau pathology in AD. <h3>Objective</h3> To study the association of regional in vivo retention of the tau PET ligand [<sup>18</sup>F]flortaucipir (previously known as AV1451) with the density of tau neuropathology in the corresponding brain regions in a patient with AD. <h3>Design, Setting, and Participants</h3> The patient was a man in his 40s with AD caused by a<i>PSEN1</i>mutation. Between May 2015 and December 2016, he underwent 2 [<sup>18</sup>F]flortaucipir PET scans at Lund University Hospital, Lund, Sweden. Postmortem analysis was performed 12 months after the last PET scan. Tau pathology was assessed using phosphorylated tau (AT8) immunohistochemistry and Gallyas silver staining. In addition to the regional total tau pathology burden, the density of tau-positive neurites and intrasomal tau tangles were quantified using a stereology-based method. Further, β-amyloid–containing plaques were detected using 4G8 immunohistochemistry. Data were analyzed between January 2018 and August 2018. <h3>Main Outcomes and Measures</h3> Regional standardized uptake value ratios of [<sup>18</sup>F]flortaucipir were compared with the amount of tau pathology in the corresponding brain areas. <h3>Results</h3> In this patient, the clinical disease symptoms progressed rapidly in life, paralleled with an annual increase of tau PET retention of 20% to 40% in many cortical regions. Compared with postmortem immunohistochemistry, regional in vivo uptake of [<sup>18</sup>F]flortaucipir was correlated with the density of tau-positive neurites (AT8:<i>r</i><sub>s</sub> = 0.87;<i>P</i> &lt; .001; Gallyas:<i>r</i><sub>s</sub> = 0.92;<i>P</i> &lt; .001), intrasomal tau tangles (AT8:<i>r</i><sub>s</sub> = 0.65;<i>P</i> = .01; Gallyas:<i>r</i><sub>s</sub> = 0.84;<i>P</i> &lt; .001), and total tau burden (AT8:<i>r</i><sub>s</sub> = 0.84;<i>P</i> &lt; .001; Gallyas:<i>r</i><sub>s</sub> = 0.82;<i>P</i> &lt; .001). No correlations between [<sup>18</sup>F]flortaucipir and β-amyloid pathology were found. <h3>Conclusions and Relevance</h3> These results indicate that [<sup>18</sup>F]flortaucipir PET retention is a robust in vivo measure of the total AD tau burden.
Patients’ education about a new service available at Memorial Sloan Kettering Multidisciplinary Clinic for frail patients with central nervous system cancers.
Authors: Elena Pentsova, Irma Purisic, Stephanie Zavolas, Anna Skakodub, Kathryn Sara Nevel, Thomas Joseph Kaley, Andrew Lin, Mariza Daras, Igor T. Gavrilovic, Lisa Marie DeAngelis, Lisa Marie Ruppert
Journal: Journal of Clinical Oncology (2018)

146 Background: A multidisciplinary clinic (MDC) is a pilot project in the MSK Department of Neurology designed to improve quality of care and patient satisfaction. The MDC enables the patient to receive coordinated care from multiple providers (eg a physical therapist, physiatrist, nutritionist, social worker, case manager, spiritual advisor, and neurologist) in one location in one longer visit. This approach is new, and few patients (pts) have had the opportunity to experience the MDC. We hypothesized that giving the patient information about the MDC will increase the MDC volume. Methods: This is a prospective quality improvement study from June 14, 2018 to July 20, 2018 conducted in four Neuro-Oncology clinics. Pts with primary or metastatic central nervous system (CNS) cancers were identified prior to the visits in their regular oncology clinic. Pts were asked if they were interested in receiving verbal or written information (brochure) about the MDC. For each patient, we recorded if they agreed to receive information, what information they received, and whether they scheduled an appointment at the MDC. We also recorded patient demographics, CNS cancer type, and whether they were accompanied by caregivers. Results: We approached 41 pts. Of the 41 pts, 31(74%) were accompanied by caregivers. Median patient age was 58 (range, 24-79) years. 26 (62%) were female. CNS cancers were primary brain tumors in 31 (76%) and brain metastases in 10 (24%). 27 (64%) of 41 pts agreed to receive both verbal information and a brochure. The remaining 14 (36%) pts did not want to receive more information about the MDC; of these, one patient didn’t take a brochure, 2 pts resided out of the country, and one patient said all needs had been addressed. Within 4 weeks of this pilot study four (15%) of 27 pts scheduled an appointment in the MDC clinic for upcoming dates. Conclusions: Among our pts with CNS tumors visiting their oncologists, 64% were willing to receive information about the MDC, four (15%) made an appointment with the MDC. More study is needed to facilitate education about and access to the MDC; to identify potential barriers; and to obtain longer follow-up.
P-glycoprotein-targeted photodynamic therapy boosts cancer nanomedicine by priming tumor microenvironment
Authors: Chengqiong Mao, Fang Li, Yan Zhao, Waldemar Debinski, Xin Ming
Journal: Theranostics (2018)

Cancer nanomedicines only modestly improve the overall survival of patients because their anticancer activity is limited by biological barriers posed by the tumor microenvironment. Currently, all the drugs in FDA-approved cancer nanomedicines are substrates for P-glycoprotein (Pgp), and thus, Pgp-mediated multidrug resistance (MDR) remains a hurdle for cancer nanomedicines. Methods: In this study, Pgp-targeted photodynamic therapy (PDT) was developed to enhance the anticancer efficacy of nanomedicines by depleting MDR cancer cells as well as enhancing tumor penetration of nanomedicines. We first examined the Pgp specificity of our targeted PDT approach, and then tested combination therapy of PDT with Doxil in mixed tumor models of MDR cancer cells and stromal cells, mimicking human heterogeneous tumors. Results:In vitro studies showed that the antibody-photosensitizer conjugates produced Pgp-specific cytotoxicity towards MDR cancer cells upon irradiation with a near-infrared light. The studies with a co-culture model of MDR cancer cells and stromal cells revealed synergistic effects in the combination therapy of PDT with Doxil. Using a mouse model of mixed tumors containing MDR cancer cells and stroma cells, we observed markedly enhanced tumor delivery of Doxil after PDT in vivo. We further examined the effects of the two modalities on individual cell populations and their synergism using an in vivo dual substrate bioluminescence assay. The results indicated that Pgp-targeted PDT specifically depleted MDR cancer cells and further enhanced Doxil's actions on both MDR cancer cells and stromal cells. Conclusion: We conclude that our targeted PDT approach markedly enhances anticancer actions of nanomedicines by depleting MDR cancer cells and increasing their tumor penetration, and thereby, may provide an effective approach to facilitate translation of cancer nanomedicines.
Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer
Authors: Gunter von Minckwitz, Chiun-Sheng Huang, Max S. Mano, Sibylle Loibl, Eleftherios P. Mamounas, Michael Untch, Norman Wolmark, Priya Rastogi, Andreas Schneeweiss, Andres Redondo, Hans H. Fischer, William Jacot, Alison K. Conlin, Claudia Arce-Salinas, Irene L. Wapnir, Christian Jackisch, Michael P. DiGiovanna, Peter A. Fasching, John P. Crown, Pia Wülfing, Zhimin Shao, Elena Rota Caremoli, Haiyan Wu, Lisa H. Lam, David Tesarowski, Melanie Smitt, Hannah Douthwaite, Stina M. Singel, Charles E. Geyer
Journal: New England Journal of Medicine (2018)

Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)–targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
Gene expression analysis of oral squamous cell carcinomas and leukoplakias
Authors: Nobuo Kondoh, Masaaki Arai, Yutaka Yamazaki, Masanobu Shindoh, Masayuki Takahashi, Mikio Yamamoto
Journal: Cancer Research (2005)

4850  Oral leukoplakias are white lesions including hyperplasia and dysplasias of oral mucosa, and some of them have been shown to undergo malignant transformation to oral squamous cell carcinoma (SCC). The dysplasias are classified into mild, moderate or severe based on histopathological findings, and thought to be the sequential phase in carcinogenesis ; however, we sometimes experience the discordance of pathological diagnosis and patients’ progress of these lesions. To classify the dysplasias and evaluate molecular mechanisms underlying the development of oral squamous cell malignancy, comprehensive gene expression profile was compared among oral SCC and leukoplakia tissues using micro array technique. Total RNAs extracted from 5 leukoplakias (a hyperplasia and 4 moderate dysplasias) and from 5 SCC tissues were mixed, respectively. Using the mixed RNAs, cDNA micro array analysis was performed based on IntelliGene HS Human Expression CHIP system (Takara, Japan). To evaluate mRNA expression, real time RT-PCR was performed using total RNAs from 26 SCCs and 16 leukoplakias (including 5 severe, 4 moderate, 6 mild displasias and 1 hyperplasia). Ninety genes were highly expressed in the SCC compared to leukoplakia mixtures, and vice versa in the expression of 56 genes. Up-regulated genes in SCCs were categorized into metabolism-related, extracellular matrix, signal transduction, INF-inducible, trafficking-associated, ubiquitin proteasome and unknown genes based on the functional significance. At least, 12 representative genes were significantly over expressed in SCCs and/or severe dysplasias compared to moderate and mild dysplasia tissues (p
Impact of patient and public involvement on enrolment and retention in clinical trials: systematic review and meta-analysis
Authors: Joanna C Crocker, Ignacio Ricci-Cabello, Adwoa Parker, Jennifer A Hirst, Alan Chant, Sophie Petit-Zeman, David Evans, Sian Rees
Journal: BMJ (2018)

Abstract Objective To investigate the impact of patient and public involvement (PPI) on rates of enrolment and retention in clinical trials and explore how this varies with the context and nature of PPI. Design Systematic review and meta-analysis. Data sources Ten electronic databases, including Medline, INVOLVE Evidence Library, and clinical trial registries. Eligibility criteria Experimental and observational studies quantitatively evaluating the impact of a PPI intervention, compared with no intervention or non-PPI intervention(s), on participant enrolment and/or retention rates in a clinical trial or trials. PPI interventions could include additional non-PPI components inseparable from the PPI (for example, other stakeholder involvement). Data extraction and analysis Two independent reviewers extracted data on enrolment and retention rates, as well as on the context and characteristics of PPI intervention, and assessed risk of bias. Random effects meta-analyses were used to determine the average effect of PPI interventions on enrolment and retention in clinical trials: main analysis including randomised studies only, secondary analysis adding non-randomised studies, and several exploratory subgroup and sensitivity analyses. Results 26 studies were included in the review; 19 were eligible for enrolment meta-analysis and five for retention meta-analysis. Various PPI interventions were identified with different degrees of involvement, different numbers and types of people involved, and input at different stages of the trial process. On average, PPI interventions modestly but significantly increased the odds of participant enrolment in the main analysis (odds ratio 1.16, 95% confidence interval and prediction interval 1.01 to 1.34). Non-PPI components of interventions may have contributed to this effect. In exploratory subgroup analyses, the involvement of people with lived experience of the condition under study was significantly associated with improved enrolment (odds ratio 3.14 v 1.07; P=0.02). The findings for retention were inconclusive owing to the paucity of eligible studies (odds ratio 1.16, 95% confidence interval 0.33 to 4.14), for main analysis). Conclusions These findings add weight to the case for PPI in clinical trials by indicating that it is likely to improve enrolment of participants, especially if it includes people with lived experience of the health condition under study. Further research is needed to assess which types of PPI work best in particular contexts, the cost effectiveness of PPI, the impact of PPI at earlier stages of trial design, and the impact of PPI interventions specifically targeting retention. Systematic review registration PROSPERO CRD42016043808.
Prognostic relevance of serum lactate kinetics in critically ill patients
Authors: Maryna Masyuk, Bernhard Wernly, Michael Lichtenauer, Marcus Franz, Bjoern Kabisch, Johanna M. Muessig, Georg Zimmermann, Alexander Lauten, P. Christian Schulze, Uta C. Hoppe, Malte Kelm, Jan Bakker, Christian Jung
Journal: Intensive Care Medicine (2018)
Reproductive Endocrinology of Nonalcoholic Fatty Liver Disease
Authors: Mathis Grossmann, Margaret E Wierman, Peter Angus, David J Handelsman
Journal: Endocrine Reviews (2018)

Abstract The liver and the reproductive system interact in a multifaceted bidirectional fashion. Sex steroid signaling influences hepatic endobiotic and xenobiotic metabolism and contributes to the pathogenesis of functional and structural disorders of the liver. In turn, liver function affects the reproductive axis via modulating sex steroid metabolism and transport to tissues via sex hormone–binding globulin (SHBG). The liver senses the body’s metabolic status and adapts its energy homeostasis in a sex-dependent fashion, a dimorphism signaled by the sex steroid milieu and possibly related to the metabolic costs of reproduction. Sex steroids impact the pathogenesis of nonalcoholic fatty liver disease, including development of hepatic steatosis, fibrosis, and carcinogenesis. Preclinical studies in male rodents demonstrate that androgens protect against hepatic steatosis and insulin resistance both via androgen receptor signaling and, following aromatization to estradiol, estrogen receptor signaling, through regulating genes involved in hepatic lipogenesis and glucose metabolism. In female rodents in contrast to males, androgens promote hepatic steatosis and dysglycemia, whereas estradiol is similarly protective against liver disease. In men, hepatic steatosis is associated with modest reductions in circulating testosterone, in part consequent to a reduction in circulating SHBG. Testosterone treatment has not been demonstrated to improve hepatic steatosis in randomized controlled clinical trials. Consistent with sex-dimorphic preclinical findings, androgens promote hepatic steatosis and dysglycemia in women, whereas endogenous estradiol appears protective in both men and women. In both sexes, androgens promote hepatic fibrosis and the development of hepatocellular carcinoma, whereas estradiol is protective.
Randomized Comparison of Power Doppler Ultrasonography-Guided Core-Needle Biopsy with Open Surgical Biopsy for the Characterization of Lymphadenopathies in Patients with Suspected Lymphoma
Authors: Novella Pugliese, Maria Di Perna, Immacolata Cozzolino, Giuseppe Ciancia, Guido Pettinato, Valeria Varone, Pio Zeppa, Stefania Masone, Claudio Cerchione, Roberta Della Pepa, Claudia Salvatore, Fabrizio Pane, Marco Picardi
Journal: Blood (2016)
Core temperature up to 41.5ºC during the UCI Road Cycling World Championships in the heat
Authors: Sebastien Racinais, Sebastien Moussay, David Nichols, Gavin Travers, Taoufik Belfekih, Yorck Olaf Schumacher, Julien D Periard
Journal: British Journal of Sports Medicine (2018)

To characterise the core temperature response and power output profile of elite male and female cyclists during the 2016 UCI Road World Championships. This may contribute to formulating environmental heat stress policies.Core temperature was recorded via an ingestible capsule in 10, 15 and 15 cyclists during the team time trial (TTT), individual time trial (ITT) and road race (RR), respectively. Power output and heart rate were extracted from individual cycling computers. Ambient conditions in direct sunlight were hot (37°C±3°C) but dry (25%±16% relative humidity), corresponding to a wet-bulb globe temperature of 27°C±2°C.Core temperature increased during all races (p<0.001), reaching higher peak values in TTT (39.8°C±0.9°C) and ITT (39.8°C±0.4°C), relative to RR (39.2°C±0.4°C, p<0.001). The highest temperature recorded was 41.5°C (TTT). Power output was significantly higher during TTT (4.7±0.3 W/kg) and ITT (4.9±0.5 W/kg) than RR (2.7±0.4 W/kg, p<0.001). Heart rate increased during the TTs (p<0.001) while power output decreased (p<0.001).85% of the cyclists participating in the study (ie, 34 of 40) reached a core temperature of at least 39°C with 25% (ie, 10 of 40) exceeding 40°C. Higher core temperatures were reached during the time trials than the RR.
Use of Dapsone in the Treatment of Chronic Idiopathic and Autoimmune Urticaria
Authors: Sydney E. Liang, Rachel Hoffmann, Erik Peterson, Nicholas A. Soter
Journal: JAMA Dermatology (2018)

The first-line treatment for patients with chronic spontaneous urticaria (CSU), which is divided into idiopathic and autoimmune subtypes, consists of H1-antihistamines. However, limited evidence guides the treatment of CSU after maximal therapy with antihistamines fails. Two randomized clinical trials suggest that dapsone may be a successful second-line therapy.To evaluate the efficacy and safety of dapsone therapy in patients with CSU.This retrospective medical record review included 79 patients with CSU treated with dapsone who presented to the tertiary care academic medical center at the New York University School of Medicine, New York, New York, from January 1, 2005, through April 15, 2017. Follow-up was completed on February 28, 2018. Data were analyzed from March 1 through May 31, 2018.Treatment with oral dapsone for CSU.Efficacy of dapsone therapy for CSU was evaluated as improvement, complete response, and remission.Seventy-nine patients (65% women; mean [SD] age, 49.8 [16.1] years [range, 20-79 years]) were included in the analysis. Forty-five patients had chronic idiopathic urticaria and 34 had chronic autoimmune urticaria. Improvement in CSU was observed in 62 patients (78%) (36 [80%] with idiopathic and 26 [76%] with autoimmune disease) with dapsone. Mean (SD) time to improvement was 1.1 (1.0) months. A complete response was achieved in 29 (47%) of these 62 patients (16 [44%] with idiopathic and 13 [50%] with autoimmune disease). Mean (SD) time to complete response was 5.2 (5.2) months. Dapsone therapy was tapered in 21 patients after a mean (SD) of 2.4 (2.2) months and discontinued in 18. Ten patients experienced remission with no subsequent flares, even after dapsone therapy was discontinued with follow-up of 0.3 to 10.0 months. Sixteen patients experienced mild adverse effects. Two serious adverse effects were reported.Results of this study suggest that dapsone is a useful and well-tolerated second-line therapy for patients with CSU in whom antihistamines and other first-line agents have failed.
Role of Der p 1–specific B cells in immune tolerance during 2 years of house dust mite–specific immunotherapy
Authors: Tadech Boonpiyathad, Willem van de Veen, Oliver Wirz, Milena Sokolowska, Beate Rückert, Ge Tan, Atik Sangasapaviliya, Panitan Pradubpongsa, Rattanaporn Fuengthong, Pattarawat Thantiworasit, Sunee Sirivichayakul, Kiat Ruxrungtham, Cezmi A. Akdis, Mübeccel Akdis
Journal: Journal of Allergy and Clinical Immunology (2018)
Prosthesis–Patient Mismatch in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Howard C. Herrmann, Samuel A. Daneshvar, Gregg C. Fonarow, Amanda Stebbins, Sreekanth Vemulapalli, Nimesh D. Desai, David J. Malenka, Vinod H. Thourani, Jennifer Rymer, Andrzej S. Kosinski
Journal: Journal of the American College of Cardiology (2018)