tbuckley/cabot-search huggingface dataset:
Capturing Exacerbations of Chronic Obstructive Pulmonary Disease with EXACT. A Subanalysis of FLAME
Authors: Stefan M. Frent, Kenneth R. Chapman, Michael Larbig, Alexander Mackay, Robert Fogel, Florian S. Gutzwiller, Steven Shen, Francesco Patalano, Donald Banerji, Konstantinos Kostikas, Jadwiga A. Wedzicha
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Chronic obstructive pulmonary disease exacerbations accelerate lung function decline, reduce quality of life, and increase mortality. A subset of patients (n = 457) from the FLAME (Effect of Indacaterol Glycopyrronium vs. Fluticasone Salmeterol on COPD Exacerbations) study used the Exacerbations of COPD Tool (EXACT) to capture symptom-defined exacerbations.To evaluate the effect of indacaterol/glycopyrronium versus salmeterol/fluticasone on symptom-defined exacerbations measured using EXACT, and to assess differences between these events and exacerbations requiring healthcare resource use (HCRU).All patients in FLAME used an electronic diary to record and detect symptom deteriorations; HCRU-related exacerbations were confirmed by investigators. In patients using the EXACT questionnaire, the onset, recovery, and magnitude of symptom-defined exacerbations were identified by changes in total scores relative to baseline. We analyzed the annualized rate and time to first symptom-defined (EXACT) exacerbation and assessed differences between symptom-defined and HCRU events in terms of number, severity, and concordance.A nonsignificant 17% reduction in the annualized rate of symptom-defined (EXACT) exacerbations (rate ratio, 0.83; 95% confidence interval [CI], 0.60-1.14; P = 0.242) and a numerically longer time to first symptom-defined exacerbation were observed with indacaterol/glycopyrronium versus salmeterol/fluticasone (hazard ratio, 0.76; 95% CI, 0.56-1.03; P = 0.075). These results were consistent with data from the overall FLAME population. Of the symptom-defined (EXACT) events, 23.5% corresponded to HCRU events, and 22.2% of HRCU events were captured by EXACT (κ index, 0.24; 95% CI, 0.15-0.33).Regardless of the exacerbation definition used, our findings support the use of long-acting β2 agonists/long-acting muscarinic receptor antagonists as the preferred treatment option for patients at risk of future exacerbations. Clinical trial registered with www.clinicaltrials.gov (NCT01782326).
Identification of Primary Congenital Hypothyroidism Based on Two Newborn Screens — Utah, 2010–2016
Authors: David E. Jones, Kim Hart, Stuart K. Shapira, Mary Murray, Robyn Atkinson-Dunn, Andreas Rohrwasser
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Newborn screening for primary congenital hypothyroidism is part of the U.S. Recommended Uniform Screening Panel (1,2). Untreated congenital hypothyroidism can result in cognitive impairment and growth complications (decreased height/length). Initial newborn screening for congenital hypothyroidism is typically performed 24-48 hours after birth. Fourteen states, including Utah, perform a routine second screen at approximately 2 weeks of age.* During 2010-2016, a total of 359,432 infants in Utah were screened for congenital hypothyroidism, and 130 cases were diagnosed; among these, 98 had an abnormal first screen, and 25 had an abnormal second screen (seven infants were excluded because of missing data). A retrospective examination of Utah's screening data indicated that 20% of congenital hypothyroidism cases could not have been efficiently identified by a single screen alone. This study highlights the utility of a two-screen process and demonstrates that differential cutoff values for the first and second screens could optimize both screening sensitivity and specificity.
Evaluation of the Pooled Cohort Risk Equations for Cardiovascular Risk Prediction in a Multiethnic Cohort From the Women’s Health Initiative
Authors: Samia Mora, Nanette K. Wenger, Nancy R. Cook, Jingmin Liu, Barbara V. Howard, Marian C. Limacher, Simin Liu, Karen L. Margolis, Lisa W. Martin, Nina P. Paynter, Paul M Ridker, Jennifer G. Robinson, Jacques E. Rossouw, Monika M. Safford, JoAnn E. Manson
Journal: JAMA Internal Medicine (2018)

Atherosclerotic cardiovascular disease (ASCVD) kills approximately 1 in every 3 US women. Current cholesterol, hypertension, and aspirin guidelines recommend calculating 10-year risk of ASCVD using the 2013 Pooled Cohort Equations (PCE). However, numerous studies have reported apparent overestimation of risk with the PCE, and reasons for overestimation are unclear. We evaluated the predictive accuracy of the PCE in the Women's Health Initiative (WHI), a multiethnic cohort of contemporary US postmenopausal women. We evaluated the effects of time-varying treatments such as aspirin and statins, and ascertainment of additional ASCVD events by linkage with the Centers for Medicare and Medicaid Services (CMS) claims. The WHI recruited the largest number of US women (n = 161 808) with the racial/ethnic, geographic, and age diversity of the general population (1993-1998). For this study, we included women aged 50 to 79 (n = 19 995) participating in the WHI with data on the risk equation variables at baseline and who met the guideline inclusion and exclusion criteria. Median follow-up was 10 years. For this study, ASCVD was defined as myocardial infarction, stroke, or cardiovascular death. Among the 19 995 women (mean [SD] age, 64 [7.3] years; 8305 [41.5%] white, 7688 [38.5%] black, 3491 [17.5%] Hispanic, 103 [0.5%] American Indian, 321 [1.6%] Asian/Pacific Islander, and 87 [0.4%] other/unknown), a total of 1236 ASCVD events occurred in 10 years and were adjudicated through medical record review by WHI investigators. The WHI-adjudicated observed risks were lower than predicted. The observed (predicted) risks for baseline 10-year risk categories less than 5%, 5% to less than 7.5%, 7.5% to less than 10%, and 10% or more were 1.7 (2.8), 4.4 (6.2), 5.3 (8.7), and 12.4 (18.2), respectively. Small changes were noted after adjusting for time-dependent changes in statin and aspirin use. Among women 65 years or older enrolled in Medicare, WHI-adjudicated risks were also lower than predicted, but observed (predicted) risks became aligned after including events ascertained by linkage with CMS for additional surveillance for events: 3.8 (4.3), 7.1 (6.4), 8.3 (8.7), and 18.9 (18.7), respectively. Similar results were seen across ethnic/racial groups. Overall, the equations discriminated risk well (C statistic, 0.726; 95% CI, 0.714-0.738). Without including surveillance for ASCVD events using CMS, observed risks in the WHI were lower than predicted by PCE as noted in several other US cohorts, but risks were better aligned after including CMS events. ClinicalTrials.gov identifier: NCT00000611.
Limitations in assessment of ER, PR, and HER2 status of breast cancer patients: Yangon experience.
Authors: Yin Yin Mon
Journal: Journal of Clinical Oncology (2012)

e11078 Background: Management of breast cancer become individualized nowadays especially in developed countries. Molecular profile of breast cancer is essential to have this management. However, there are still limitations to examine such molecular profile in developing countries like Myanmar. Our aim in this study is to know the number of patients who underwent ER, PR and HER 2 status assessment among breast cancer patients in Myanmar and to analyze types of limitations for the molecular assessment in management of breast cancer. Methods: Total number of 823 breast cancer patients who registered from January 2009 to December 2011 at Medical Oncology Unit of Yangon General Hospital and two private oncology clinics were studied. Results: The age range from 19-80 years and mean age of 44.36 years. Among 823 breast cancer patients, ER, PR and HER 2 status were done in 134 patients (16.28% ) whereas 689 patients( 83.71% ) were not. 604 (87.66%) out of 689 patients who did not undergo profiling were due to financial problem. 60 patients (8.70 %) were found to have lack of information about molecular profiling although they were affordable . 25 patients (3.62 %) lost their tissue due to technological limitation Conclusions: Financial problem is the major limitation to get molecular profile for breast cancer patients in Myanmar. Patients need self expense to do advanced technology examinations in different health care system of our country. In this study we also found out that there was lack of information which leads not to undergo further investigations to some well to do patients. Overall, we believe that molecular technology support with reduced expense will help more patients in future to get better management in breast cancer in Myanmar. Besides, we need to provide update information about molecular testing in breast cancer to not only patients but also health professionals in our country.
Abstract 14195: Physiological Ventilation Volume Improves Return of Spontaneous Circulation in a Pig Model of Eight-minute Untreated Cardiac Arrest
Authors: Dingyu Tan, Yangyang Fu, Shihuan Shao, Feng Sun, Jun Xu, Huadong Zhu, Xuezhong Yu
Journal: Circulation (2016)

Background:  It is not known whether the duration of cardiac arrest affects the ventilatory requirements during CPR.   Hypothesis:  For prolonged cardiac arrest, current recommended ventilation pattern is nonideal for satisfactory results during CPR.   Methods:  In 32 pigs (intubated and ventilated with a tidal volume of 10 mL/kg and a frequency which maintained P ET CO 2    between 35 and 40 mmHg), ventricular fibrillation (VF) was induced and chest compressions (CC) were started after 4min or 8min. Sixteen pigs of 4min VF randomly received mechanical ventilation with a tidal volume of 7 mL/kg and a frequency of 10/min (Guideline-4, n=8) or the same tidal volume and frequency as baseline (Baseline-4, n=8). Sixteen pigs of 8min VF had similar groups (Guideline-8 and Baseline-8). Following 10min uninterrupted CC and mechanical ventilation, up to three defibrillations was administered. Measurements were taken at baseline, 5th and 10th minute of CC.   Results:  Ventilation in Baseline-4 (minute ventilation 5.7±1.0 L/min) resulted in higher PHa, PaO 2 , mean airway pressure, and lower PaCO 2 , SvO2, and P ET CO 2  than Guideline-4 (2.3±0.4 L/min) both at the 5th and 10th minute of CC ( p  p  2 , PHv, mean airway pressure, and lower PaCO 2  and PvCO 2  than Guideline-8 (2.4±0.5 L/min) both at the 5th and 10th minute ( p   Hemodynamic parameters were not statistically different between two groups of 8min VF ( p  p =0.039).   Conclusions:  For 4min VF pig models, guideline-based ventilation was proper during CPR, however, physiological ventilation volume resulted in higher ROSC during CPR for 8min VF.
Abstract 16232: Lipoprotein(a) is Not Associated With the Risk of Ischemic Cardiovascular Events Following Acute Coronary Syndrome
Authors: Gregory G Schwartz, Christie M Ballantyne, Philip J Barter, David Kallend, Eran Leitersdorf, Lawrence A Leiter, John J McMurray, Stephen J Nicholls, Anders G Olsson, Reynaria Pitts, Prediman K Shah, Jean-Claude Tardif, John Kittelson
Journal: Circulation (2016)

Background: Lipoprotein(a) [Lp(a)] is associated with incident cardiovascular (CV) risk in observational cohorts, but it is unclear whether Lp(a) is an independent risk factor for recurrent CV even...
Abstract 14385: Novel STORM-based Quantitative Nanoscale Assessment Reveals Two Pools of Sodium Channels Within the Cardiac Intercalated Disk
Authors: Rengasayee Veeraraghavan, Robert G Gourdie
Journal: Circulation (2016)

Background:  The spatial association between proteins is crucial to understanding how proteins function in biological systems. Colocalization assessed from diffraction-limited fluorescence microscopy images merely indicates that the proteins are within 200-300 nm of each other in the xy plane and within 500-700 nm of each other along the z-axis. We sought to develop a method applicable to single molecule positional data from super-resolution STochastic Optical Reconstruction Microscopy (STORM) which achieves resolutions of 20 nm laterally and    Methods and Results:  To this end, we developed STORM-based Relative Localization Analysis (STORM-RLA) which quantifies the spatial relationship between clusters of co-labeled proteins: 1) the instance and degree of overlap between clusters, and, 2) the distance from each cluster to the nearest cluster of the co-labeled protein. Here, we apply STORM-RLA, a novel, 3-dimensional quantitative analysis, to analyze sodium channel (Na V 1.5) localization relative to connexin43 (Cx43) and N-cadherin (N-Cad) within the intercalated disk (ID) in guinea pig ventricular myocardium. Examination of 2190 Na V 1.5 clusters and 1767 Cx43 clusters revealed that 17% of Na V 1.5 clusters overlapped a Cx43 clusters; however, 31% was located less than 200 nm from a Cx43 cluster. Overlap, where it occurred, involved 22 ± 4% of the Na V 1.5 and 35 ± 7% of the Cx43 clusters. Overall, 61% of Cx43 clusters had Na V 1.5 less than 200 nm away, with a median distance of 75 ± 25 nm. In contrast, 30% of Na V 1.5 clusters and 29% of N-Cad clusters overlapped with each other across 2030 Na V 1.5 clusters and 1768 N-Cad clusters examined with a median distance of 77 ± 19 nm. Overlap, where it occurred, involved 48 ± 7% of the Na V 1.5 and 43 ± 5% of the N-Cad clusters. Immuno-electron microscopy quantitatively confirmed segregation of Na V 1.5 between these two junction-associated ID nanodomains.   Conclusions:  Two pools of Na V 1.5 may exist within the ID: one adjacent Cx43 GJ located in interplicate ID regions and another co-distributed with N-cadherin within plicate ID regions. Overall, STORM-RLA represents a significant advance in the high throughput quantitative assessment of the spatial organization of proteins.
EuroPrevall: insights into the allergic disease epidemic
Authors: Caroline J Lodge, Adrian J Lowe, Shyamali C Dharmage
Journal: Thorax (2018)

‘Asthma’ is now recognised as an umbrella term that includes a heterogeneous group of phenotypes whose aetiology and prognosis vary. This heterogeneity is even more significant in asthma diagnosed before 5 years, using the symptom of wheeze as the predominant criterion, even though not all wheeze is asthma. Therefore, wheezing, which is common in preschool children, is often incorrectly labelled as asthma. Two pragmatic clinical phenotypes1 with distinct risk factors2 3 have been used to describe early life wheeze and assist in determining asthma in early childhood: episodic viral wheeze (EVW) and multitrigger wheeze (MTW). Prognosis is good in recurrent mild EVW although remission is uncommon in atopic MTW and children usually go on to develop asthma. Care should be taken when using these categories, as individual children can change category over time.1 Cohort studies have also described phenotypes of early childhood wheeze by using changing ‘asthma’ symptoms with age and determining distinct patterns in underlying groups (using latent class analysis and latent class growth analysis). These include investigations on cohorts using either symptoms of wheeze (the Melbourne Atopy Cohort Study (MACS),4 5 the Avon Longitudinal Study of Parents and Children (ALSPAC),6 the Prevention and Incidence of Asthma and Mite Allergy (PIAMA)7 (Columbia Center for Children’s Environmental Health)8) or symptoms of wheeze and cough (the Leicestershire cohort9). The aetiology and prognosis of each of these phenotypes have been found to vary significantly with many early life factors including gender, atopy, eczema, parental allergic disease, breast feeding, exposure to tobacco smoke, siblings, exposure to pets, day care attendance, respiratory tract infections and body mass index. Risk factors associated with each phenotype, however, show similar findings across all these analyses independent of populations …
Voltage-Gated K+ Currents Regulate Resting Membrane Potential and [Ca2+]i in Pulmonary Arterial Myocytes
Authors: Xiao-JianYuan
Journal: Circulation Research (1995)

Abstract The membrane potential (Em) of pulmonary arterial smooth muscle cells (PASMCs) regulates pulmonary arterial tone by controlling voltage-gated Ca2+ channel activity, which is a major contributor to [Ca2+]i. The resting membrane is mainly permeable to K+; thus, the resting Em is controlled by K+ permeability through sarcolemmal K+ channels. At least three K+ currents, voltage-gated K+ (KV) currents, Ca2+-activated K+ (KCa) currents, and ATP-sensitive (KATP) currents, have been identified in PASMCs. In this study, both patch-clamp and quantitative fluorescent microscopy techniques were used to determine which kind(s) of K+ channels (KV, KCa, and/or KATP) is responsible for controlling Em and [Ca2+]i under resting conditions in rat PASMCs. When the bath solution contained 1.8 mmol/L Ca2+ and the pipette solution included 0.1 mmol/L EGTA, depolarizations (−40 to +80 mV) elicited both KCa and KV currents. Removal of extracellular Ca2+ and increase of intracellular EGTA concentration (to 10 mmol/L) elim...
Open-label, phase II trial of afatinib, with or without vinorelbine (V), for the treatment of HER2-overexpressing inflammatory breast cancer (IBC).
Authors: Charles Swanton, Jamie Cromer
Journal: Journal of Clinical Oncology (2012)

TPS650 Background: IBC is an aggressive and rare form of BC (1–6% cases). Despite recent treatment advances, prognosis remains poor, with 3-yr survival rate of 40 vs 85% in non-IBC. IBC commonly lack ER/PR and more frequently harbour HER2 gene ampliﬁcation (~40%), and EGFR overexpression (~30%) associated with poor prognosis. Recent data reported clinical efficacy of lapatinib, a reversible EGFR/HER2 inhibitor, in trastuzumab (T) naïve/resistant HER2 positive IBC. Afatinib is an irreversible ErbB Family Blocker with preclinical activity in T-resistant cell lines, HER2-positive tumor xenografts and HER2-negative SUM 149 xenograft model derived from an IBC cell line. Its clinical efficacy was shown in heavily pre-treated, HER2-positive metastatic BC pts who progressed after T, with PR in 10% and clinical benefit in 46% of pts. The purpose of this biomarker-driven study is to investigate efficacy and safety of afatinib alone and in combination with V upon progression on afatinib monotherapy and the genomic changes that occur through treatment in pts with T pretreated or naïve HER2-positive IBC. Methods: Pts are recruited in 2 parallel cohorts of 20 pts each: T-naïve and T failure. Key eligibility criteria: histologically-confirmed HER2-positive BC; investigator-confirmed IBC characterized by diffuse erythema and oedema (peau d’orange) while dermal lymphatic emboli or palpable mass are not necessary for diagnosis; no prior anti-HER2 therapy except T in the T failure cohort; no prior V; ECOG 0–2. All pts start afatinib monotherapy (40 mg/d oral) in 4-week cycles (Part A). Upon disease progression, pts may receive afatinib (40 mg/d) + V (IV 25 mg/m 2 /week) (Part B). Primary endpoint: Clinical Benefit Rate (CR, PR or SD) for ≥6 months. Secondary endpoints: objective response rate, PFS, OS and safety. Endpoints are assessed separately for Part A and Part B. Fresh biopsy and blood samples are taken prior to treatment and upon progression in Part A, to explore predictive markers of response/resistance to afatinib, to describe the IBC population which may benefit most, and for next generation sequencing and proteomic analysis. Enrollment ongoing since Aug 2011.
Understanding variation in prevalence estimates of polycystic ovary syndrome: a systematic review and meta-analysis
Authors: Marina A Skiba, Rakibul M Islam, Robin J Bell, Susan R Davis
Journal: Human Reproduction Update (2018)

Polycystic ovary syndrome (PCOS) prevalence estimates vary when different diagnostic criteria are applied. Lack of standardization of individual elements within these criteria may contribute to prevalence differences. A systematic review of studies reporting prevalence of PCOS, using at least one of the National Institutes of Health (NIH), Rotterdam or Androgen Excess Society (AE-PCOS) criteria, was conducted. The aim was to investigate the impact on prevalence reporting of different definitions of the clinical elements for PCOS diagnosis. A systematic search of Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Emcare and BIOSIS was conducted. The search was limited to English language and studies published between January 1990 and January 2018. Included articles needed to define PCOS by at least one of the NIH, Rotterdam or AE-PCOS criteria, be of an unselected population and be published as a full text article. Risk-of-bias was assessed. A total of 21 studies met the inclusion criteria. The random-effects pooled prevalence of PCOS in studies that used the NIH criteria (7% [95% CI: 6–7%]), was significantly different from that identified in studies that used the Rotterdam criteria (12% [95% CI: 10–15%], P < 0.0001) but not studies that used the AE-PCOS criteria (10% [95% CI: 6–13%], P = 0.075). The pooled estimates for Rotterdam and AE-PCOS were not significantly different from each other (P = 0.201). Pooled prevalence estimates were compared between studies separated on the basis of: oligo-amenorrhoea vs oligo-amenorrhoea plus short cycles, clinical androgen excess requiring hirsutism vs any clinical androgen excess, use of different versions and cut-offs for the Ferriman–Gallwey (F–G) score, and inclusion vs non-inclusion of oral contraceptive users. There were no statistically significant differences for any of these comparisons. There was insufficient information to allow subgroup analyses of definitions of polycystic ovaries. Inclusion of ovarian morphology results in statistically significantly higher pooled prevalence estimates for PCOS. Heterogeneity in prevalence estimates for PCOS reflect the broad clinical spectrum of the condition, lack of standardization of the elements within each set of diagnostic criteria and the use of a range of diagnostic cut-offs, as well as potential differences between study populations. The use of different definitions for anovulation and clinical androgen excess did not appear to contribute to differences in the estimated prevalence of PCOS in this study. However, as the number of studies in most of the comparison groups was small, real differences may have been missed. Uncertainty surrounding the diagnosis of PCOS urgently needs to be addressed in order to provide clinicians and their patients with greater diagnostic certainty, and hence reduce inappropriate labelling and the potential psychological harm that may accompany misdiagnosis.
Tumor microenvironment participates in metastasis of pancreatic cancer
Authors: Bo Ren, Ming Cui, Gang Yang, Huanyu Wang, Mengyu Feng, Lei You, Yupei Zhao
Journal: Molecular Cancer (2018)

Pancreatic cancer is a deadly disease with high mortality due to difficulties in its early diagnosis and metastasis. The tumor microenvironment induced by interactions between pancreatic epithelial/cancer cells and stromal cells is critical for pancreatic cancer progression and has been implicated in the failure of chemotherapy, radiation therapy and immunotherapy. Microenvironment formation requires interactions between pancreatic cancer cells and stromal cells. Components of the pancreatic cancer microenvironment that contribute to desmoplasia and immunosuppression are associated with poor patient prognosis. These components can facilitate desmoplasia and immunosuppression in primary and metastatic sites or can promote metastasis by stimulating angiogenesis/lymphangiogenesis, epithelial-mesenchymal transition, invasion/migration, and pre-metastatic niche formation. Some molecules participate in both microenvironment formation and metastasis. In this review, we focus on the mechanisms of pancreatic cancer microenvironment formation and discuss how the pancreatic cancer microenvironment participates in metastasis, representing a potential target for combination therapy to enhance overall survival.