tbuckley/cabot-search huggingface dataset:
Risk of malignancy associated with paediatric use of tumour necrosis factor inhibitors
Authors: Timothy Beukelman, Fenglong Xie, Lang Chen, Daniel B Horton, James D Lewis, Ronac Mamtani, Melissa M Mannion, Kenneth G Saag, Jeffrey R Curtis
Journal: Annals of the Rheumatic Diseases (2018)

To determine whether tumour necrosis factor inhibitor (TNFi) use is associated with an increased rate of incident malignancy compared with no TNFi use in the treatment of juvenile idiopathic arthritis (JIA), paediatric inflammatory bowel disease (pIBD) and paediatric plaque psoriasis (pPsO).We performed a retrospective cohort study of administrative claims data from the USA from 2000 to 2014. Exposure to TNFi was considered permanent from the first observed exposure onward. The malignancy outcome was defined by diagnosis codes with evidence of cancer treatment. We calculated standardised incidence ratios (SIRs) comparing the observed number of malignancies to the expected numbers according to cancer surveillance data. We used multivariable Cox proportional hazards models to estimate adjusted HRs (aHRs) for incident malignancy.We identified 15 598 children with TNFi use and 73 839 children with no TNFi use (30 703 and 121 801 person-years of follow-up, respectively). We identified 15 malignancies among children with TNFi use (SIR 2.9 (1.6 to 4.9)) and 42 malignancies among children without TNFi use (SIR 2.1 (1.5 to 2.9)). The aHR was 1.58 (0.88 to 2.85) for TNFi use versus no TNFi use. In pIBD, TNFi use with thiopurine use was associated with a higher SIR (6.0 (1.2 to 17.5)) compared with TNFi use without thiopurine use (2.5 (0.7 to 6.4)).Children diagnosed with JIA, pIBD and pPsO had an increased rate of malignancy compared with the general population, but treatment with TNFi did not appear to significantly further increase the risk compared with no TNFi use. More data are needed about the long-term risks of TNFi use.
Role of nurse navigator in completion of multi-modality rectal cancer treatment.
Authors: Sulochana Devi Cherukuri, Anita Kumari, Salini Sathya Naidu, Judy B. Koutlas, Paul R. Walker, Pamela A. Lepera, Prashanti Atluri
Journal: Journal of Clinical Oncology (2014)

e17651 Background: Standard treatment of stage II/III rectal cancer includes neoadjuvant CRT followed by surgery and postoperative adjuvant chemotherapy. A significant proportion of patients with rectal cancer do not complete their postoperative treatment plan, which has a great impact on disease outcomes. The utilization of a Nurse Navigator (NN) to assist in the completion and adherance to adjuvant chemotherapy is one way to accomplish this. We looked at the completion of post operative adjuvant therapy in patients at our institution prior to and after hiring an NN. Methods: Our study design includes a retrospective review of patients from Jan 2006 to Feb 2013 from our Institutional data base at Leo Jenkins Cancer Center. A total of 43 patients diagnosed with locally advanced rectal cancer treated with neoadjuvant CRT followed by resection were identified. Data points analyzed included demographics, stage, neoadjuvant therapy, surgery, number of patients before who received and completed adjuvant therapy prior to and after an NN was involved. Results: See Table. Conclusions: Using an NN to assist in the care of rectal cancer patients increased the number of patients who were initiated on post-op adjuvant therapy; 65% vs. 74%. In addition, fewer number of patients discontinued treatment; 35% vs. 61%. In this retrospective study, though the sample size is small, we were able to show that utilization of an NN increased the number of patients initiated on adjuvant rectal cancer treatment as well as the likelihood of adherence to therapy. Of interest, the initiation of adjuvant therapy at our institution was higher than the average of 40% reported at larger institutions, whether or not an NN was involved. With NN Without NN Adjuvant Therapy (Initiated) 17(74%) 13(65%) No Adjuvant Therapy 6(26%) 7(35%) Adjuvant Therapy Discontinued 6(35%) 8(61%) Total Patients 23 20
Abstract P093: Influence of Comorbidities on Outcomes in Atrial Fibrillation: A Population-based Case-control Study
Authors: Alanna Chamberlain, Alvaro Alonso, Bernard Gersh, Sheila Manemann, Jill Killian, Susan Weston, Veronique Roger
Journal: Circulation (2016)

Background: Differences in the impact of comorbid conditions on outcomes in atrial fibrillation (AF) patients compared to population controls have not been well documented. Methods: The prevalence of 19 chronic conditions and smoking status was obtained in 1430 patients with incident AF from 2000-2010 and 1430 controls matched 1:1 on sex and age (within 5 years) from Olmsted County, MN. Andersen-Gill models determined associations of each condition with all-cause hospitalizations in AF cases and controls after adjusting for all other conditions and accounting for the matching. Cox regression determined associations of each condition with death. Results: Among 1430 matched pairs (median age 76 years, 48.6% men), the prevalence of chronic conditions was higher in AF cases compared to controls for all conditions except asthma, dementia, depression, hepatitis, and osteoporosis. Over a mean follow-up of 6.3 years, 2678 hospitalizations and 812 deaths occurred. The rates of hospitalization were 59 and 26 per 100 person-years and the rates of death were 10 and 5 per 100 person-years in AF cases and controls, respectively. After adjusting for all other conditions, the risk of hospitalization was lower in AF patients compared to controls for those with coronary artery disease, arthritis, cancer, chronic obstructive pulmonary disease, and osteoporosis (figure). In contrast, the risk of hospitalization was higher in AF cases for those with diabetes and substance abuse. For deaths, the only comorbidity with different associations between AF cases and controls was depression. The hazard ratios (95% CI) for death were 2.02 (1.26-3.24) in AF cases and 0.90 (0.58-1.38) in controls (p-value for interaction=0.008). Conclusions: AF patients have a higher prevalence of chronic conditions compared to population controls. The associations of comorbidities with hospitalizations differed between AF cases and controls, suggesting that management of comorbidities in patients with AF may need to be tailored to this specific patient population.
Combined endoscopic submucosal dissection and transanal minimally invasive surgery for resection of large refractory rectal polyp
Authors: Sandy Fang, Saowanee Ngamruengphong
Journal: Endoscopy (2018)

See also: Comments on “Combined endoscopic submucosal dissection and transanal minimally invasive surgery for resection of large refractory rectal polyp”Endoscopy 2019; 51(03): 281-281DOI: 10.1055/a-0826-4558
The DISCOVER Study 3-Year Results
Authors: Justis P Ehlers, Yasha S Modi, Paula E Pecen, Jeff Goshe, William J Dupps, Aleksandra Rachitskaya, Sumit Sharma, Alex Yuan, Rishi Singh, Peter K Kaiser, Jamie L Reese, Carmen Calabrise, Allison Watts, Sunil K Srivastava
Journal: Ophthalmology (2018)
Rhinovirus causes increased acute symptoms in children with first time wheezing compared to either controls with cold symptoms or children with first time wheezing and Respiratory Syncytial Virus
Authors: Ashley Stoner, Darrell L. Dinwiddie, Claire C. Putt, Kurt Schwalm, John C. Kincaid, Mallory Bell, Thomas J. Abramo, Tonya M. Thompson, Stacie M. Jones, Richard C. Kurten, Joshua L. Kennedy
Journal: Journal of Allergy and Clinical Immunology (2018)
Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies
Authors: Leo Sheck, Wayne I.L. Davies, Phillip Moradi, Anthony G. Robson, Neruban Kumaran, Alki C. Liasis, Andrew R. Webster, Anthony T. Moore, Michel Michaelides
Journal: Ophthalmology (2018)

PurposeTo investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children.DesignRetrospective case series.ParticipantsPatients with mutations in CEP290 identified at a single UK referral center.MethodsReview of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing.Main Outcome MeasuresMolecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment.ResultsForty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features.ConclusionsDetailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches.
HER2 antibodies pertuzumab and trastuzumab differ in their effect on cell signaling and growth inhibition in breast cancer cells
Authors: Xiaofeng Le, Weiqun Mao, Yiling Lu, Gordon B. Mills, Robert C. Bast
Journal: Cancer Research (2006)

3836  HER2 overexpression occurs in about 20-30% of breast cancers and is associated with a poor prognosis. Therapy with the anti-HER2 antibody trastuzumab has significantly improved the outcome of patients with breast cancers that overexpress HER2. A novel anti-HER2 antibody, pertuzumab binds to domain II of HER2, whereas trastuzumab binds to domain IV. Here we report that pertuzumab almost completely blocks heregulin-induced HER3-p85 association with PI3K, AKT activation, and ERK1/2 activation, whereas trastuzumab only partially reduces heregulin-induced HER3-p85 association and activation of AKT or ERK1/2. Trastuzumab inhibits by 40% the anchorage-dependent growth of BT474 and SKBr3 cells that overexpress HER2 in vitro, but had no effect on cell growth of T47D and MCF-7 cells that express low levels of HER2. Pertuzumab had no inhibitory effect on each of the four cell lines in vitro in the absence of heregulin stimulation. Pertuzumab did, however, block heregulin-stimulated cell proliferation of T47D. In contrast to trastuzumab, pertuzumab did not inhibit CDK2, induce p27Kip1 or induce G1 arrest of the cell cycle in BT474 or SKBr3 cells. Using protein lysates array, trastuzumab was found to reduce activation of AKT, p70S6K, and 4EBP-1. In contrast, pertuzumab did not inhibit activation of AKT, p70S6K, and 4EBP-1 in either BT474 or SKBr3 cells. By using biotinalized-trastuzumab, biotinalized-pertuzumab, and streptoavidin-FITC, both trastuzumab and pertuzumab were found to internalize slowly, although trastuzumab internalized slightly faster than pertuzumab. After 16-48 hrs at 37 degrees Celsius, 96.7% of pertuzumab-treated SKBr3 cells were still surface-FITC positive with a fluorescent intensity of 65, whereas 93% of trastuzumab-treated cells were surface-FITC positive with a fluorescent intensity of 64. Trastuzumab could not block the binding sites of pertuzumab. Anti-HER2 monoclonal antibodies TA1 and ID5 could block neither trastuzumab nor pertuzamab binding sites, whereas 4D5 completely block trastuzumab-binding sites as expected. Like trastuzumab, pertuzumab inhibited invasion of breast cancer cells. In conclusion, HER2 antibodies pertuzumab and trastuzumab differ in their effect on cell signaling and growth inhibition in breast cancer cells.
A controlled human malaria infection model enabling evaluation of transmission-blocking interventions
Authors: Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Melanie Rampton, Suzanne Elliott, Isaie J. Reuling, Teun Bousema, Robert Sauerwein, Stephan Chalon, Jörg J. Möhrle, James S. McCarthy
Journal: Journal of Clinical Investigation (2018)

Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here, we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI).Seventeen healthy malaria-naive volunteers underwent CHMI by intravenous inoculation of P. falciparum-infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation, participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary end points were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), or a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage.Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8 of 11 (73%) participants evaluated. Compared with results in untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe - fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase - and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention.We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naive volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for evaluating transmission-blocking interventions in this model.ClinicalTrials.gov NCT02431637 and NCT02431650.Bill & Melinda Gates Foundation.
Course of Cognitive Development From Infancy to Early Adulthood in the Psychosis Spectrum
Authors: Josephine Mollon, Anthony S. David, Stanley Zammit, Glyn Lewis, Abraham Reichenberg
Journal: JAMA Psychiatry (2018)

Most patients with psychotic disorders experience severe cognitive impairment, but the onset and course of this impairment remain unclear. Moreover, the course of cognitive functions in other psychiatric conditions remains largely unexamined.To chart the course of general and specific cognitive functions in individuals with psychotic disorders, psychotic experiences, and depression.The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective cohort study comprising all live births between April 1, 1991, and December 31, 1992, in Avon, England. The dates of analysis were September 2015 to July 2016. Participants who underwent cognitive testing at ages 18 months and 4, 8, 15, and 20 years and psychiatric assessment at age 18 years were included.Individuals with psychotic disorder, psychosis with depression, psychotic experiences, and depression were compared with controls. Outcomes were full-scale, verbal, and nonverbal IQ at ages 18 months and 4, 8, 15, and 20 years, as well as measures of processing speed, working memory, language, visuospatial ability, and attention at ages 8 and 20 years.The following numbers of individuals were available for analyses in this longitudinal birth cohort study: 511 (238 male [46.6%]) at age 18 months (mean [SD] age, 1.53 [0.03] years), 483 (229 male [47.4%]) at age 4 years (mean [SD] age, 4.07 [0.03] years), 3930 (1679 male [42.7%]) at age 8 years (mean [SD] age, 8.65 [0.29] years), 3783 (1686 male [44.6%]) at age 15 years (mean [SD] age, 15.45 [0.27] years), and 257 (90 male [35.0%]) at age 20 years (mean [SD] age, 20.06 [0.55] years). Individuals with psychotic disorder showed continually increasing deficits between infancy (18 months) and adulthood (20 years) in full-scale IQ (effect size of change [ESΔ] = -1.09, P = .02) and nonverbal IQ (ESΔ = -0.94, P = .008). The depression group showed a small, increasing deficit in nonverbal IQ (ESΔ = -0.29, P = .04) between infancy and adulthood. Between ages 8 and 20 years, the psychotic disorder group exhibited developmental lags (ie, slower growth) in measures of processing speed (ESΔ = -0.68, P = .001), working memory (ESΔ = -0.59, P = .004), and attention (ESΔ = -0.44, P = .001) and large, static deficits in measures of language (ES = -0.87, P = .005) and visuospatial ability (ES = -0.90, P = .001). There was only weak evidence for cognitive deficits in the psychosis with depression group and the psychotic experiences group.The findings herein suggest that the origins of psychotic disorder involve dynamic developmental processes, affecting both verbal and nonverbal abilities throughout the first 2 decades of life and leading to increasing dysfunction. These developmental processes do not manifest in other psychiatric disorders, such as psychosis with depression and depression.
Eradication of spontaneous malignancy by local immunotherapy
Authors: Idit Sagiv-Barfi, Debra K. Czerwinski, Shoshana Levy, Israt S. Alam, Aaron T. Mayer, Sanjiv S. Gambhir, Ronald Levy
Journal: Science Translational Medicine (2018)

In situ vaccination with low doses of TLR ligands and anti-OX40 antibodies can cure widespread cancers in preclinical models.
FoxO transcription factors are required for hepatic HDL cholesterol clearance
Authors: Samuel X. Lee, Markus Heine, Christian Schlein, Rajasekhar Ramakrishnan, Jing Liu, Gabriella Belnavis, Ido Haimi, Alexander W. Fischer, Henry N. Ginsberg, Joerg Heeren, Franz Rinninger, Rebecca A. Haeusler
Journal: Journal of Clinical Investigation (2018)

Insulin resistance and type 2 diabetes are associated with low levels of high-density lipoprotein cholesterol (HDL-C). The insulin-repressible FoxO transcription factors are potential mediators of the effect of insulin on HDL-C. FoxOs mediate a substantial portion of insulin-regulated transcription, and poor FoxO repression is thought to contribute to the excessive glucose production in diabetes. In this work, we show that mice with liver-specific triple FoxO knockout (L-FoxO1,3,4), which are known to have reduced hepatic glucose production, also have increased HDL-C. This was associated with decreased expression of the HDL-C clearance factors scavenger receptor class B type I (SR-BI) and hepatic lipase and defective selective uptake of HDL cholesteryl ester by the liver. The phenotype could be rescued by re-expression of SR-BI. These findings demonstrate that hepatic FoxOs are required for cholesterol homeostasis and HDL-mediated reverse cholesterol transport to the liver.
TMC Proteins Modulate Egg Laying and Membrane Excitability through a Background Leak Conductance in C. elegans
Authors: Xiaomin Yue, Jian Zhao, Xiao Li, Yuedan Fan, Duo Duan, Xiaoyan Zhang, Wenjuan Zou, Yi Sheng, Ting Zhang, Qian Yang, Jianhong Luo, Shumin Duan, Rui Xiao, Lijun Kang
Journal: Neuron (2018)
Mid- and Long-Term Health Risks in Living Kidney Donors
Authors: Linda M. O'Keeffe, Anna Ramond, Clare Oliver-Williams, Peter Willeit, Ellie Paige, Patrick Trotter, Jonathan Evans, Jonas Wadström, Michael Nicholson, Dave Collett, Emanuele Di Angelantonio
Journal: Annals of Internal Medicine (2018)

Long-term health risks for adults who donate kidneys are unclear.To summarize evidence about mid- and long-term health risks associated with living kidney donation in adults.PubMed, Embase, Scopus, and PsycINFO without language restriction from April 1964 to July 2017.Observational studies with at least 1 year of follow-up that compared health outcomes in adult living kidney donors versus nondonor populations.Two investigators independently extracted study data and assessed study quality.52 studies, comprising 118 426 living kidney donors and 117 656 nondonors, were included. Average follow-up was 1 to 24 years. No evidence suggested higher risk for all-cause mortality, cardiovascular disease, hypertension, type 2 diabetes, or adverse psychosocial health outcomes in living kidney donors than in nondonor populations. Donors had higher diastolic blood pressure, lower estimated glomerular filtration rates, and higher risk for end-stage renal disease (ESRD) (relative risk [RR], 8.83 [95% CI, 1.02 to 20.93]) and preeclampsia in female donors (RR, 2.12 [CI, 1.06 to 4.27]). Despite the increased RR, donors had low absolute risk for ESRD (incidence rate, 0.5 event [CI, 0.1 to 4.9 events] per 1000 person-years) and preeclampsia (incidence rate, 5.9 events [CI, 2.9 to 8.9 events] per 100 pregnancies).Generalizability was limited by selected control populations, few studies reported pregnancy-related outcomes, and few studies were from low- and middle-income countries.Although living kidney donation is associated with higher RRs for ESRD and preeclampsia, the absolute risk for these outcomes remains low. Compared with nondonor populations, living kidney donors have no increased risk for other major chronic diseases, such as type 2 diabetes, or for adverse psychosocial outcomes.National Health Service Blood and Transplant and National Institute for Health Research. (PROSPERO: CRD42017072284).
Assay variation in the detection of antinuclear antibodies in the sera of patients with established SLE
Authors: David S Pisetsky, Diane M Spencer, Peter E Lipsky, Brad H Rovin
Journal: Annals of the Rheumatic Diseases (2018)

The expression of antinuclear antibodies (ANA) is considered almost constant in systemic lupus erythematosus (SLE), although recent experience has suggested that many subjects with SLE considered for clinical trials are ANA negative at screening. The objective of this study is to determine whether assay variation can influence ANA detection in patients with established SLE.Sera from 103 patients with established SLE were tested using three different immunofluorescence assays (IFA) for ANA determination. ANA determinations were also performed by an ELISA and bead-based multiplex assay.With IFA kits, the frequency of ANA negativity varied from 5 to 23 of 103 samples (4.9%-22.3%). The ELISA and multiplex assays showed that 12 (11.7%) and 14 (13.6%) samples were negative, respectively. Samples positive in all assays differed from those with discordant assay results in the frequency of historical anti-double-stranded DNA positivity and low complement levels at the time of blood sampling.These findings indicate that ANA negativity occurs in patients with established SLE although the frequency varies depending on the assay kit. Given the range of negativity with well-validated assays, these findings raise questions about whether ANA positivity should be employed to determine eligibility for clinical trials.