tbuckley/cabot-search huggingface dataset:
Assessing process, content, and politics in developing the global health sector strategy on sexually transmitted infections 2016–2021: Implementation opportunities for policymakers
Authors: Andy Seale, Nathalie Broutet, Manjulaa Narasimhan
Journal: PLoS Medicine (2017)

Sexually transmitted infections (STIs) present significant health and economic challenges in all countries and yet are rarely prioritised for coordinated strategic attention.• The 2016 World Health Assembly adopted a global health sector strategy on STIs for 2016-2021, including ambitious 2020 and 2030 goals aligned with broader sustainable development goals and targets of ending disease epidemics as public health concerns by 2030.• The strategy requires actions at the country level, guided and led by governments, supported by the World Health Organization (WHO) and other partners.• A number of barriers frustrate efforts to take the response to STIs to scale, including insufficient incidence data and disease surveillance, and political resistance to scientifically-proven and often cost-effective interventions and approaches.• Country-level success in strategy implementation requires that WHO, Ministries of Health, and broader stakeholders look beyond the interventions required for effective STI management to also consider the broader context, processes, and politics of STIs when building and strengthening responses.• Evaluating progress towards the strategy's 2020 coverage targets and 2030 coverage and impact targets will be the key success-measurement tool, yet limiting analysis to the frame of coverage and impact targets alone will deny important opportunities to drive action and to evolve policies and programmes in dynamic contexts.• Exploring and assessing the implementation context, political interest, and potential of health policies can ensure early identification of challenges and opportunities when focused on national-level policy uptake and execution.• This paper applies an analytical approach to the global strategy that includes an investigation of 3 domains: process, programmatic, and political.Key questions are proposed to guide exploration of these domains to help identify and address barriers to, and leverage solutions for, policy success.
Fluorescent visualisation of collagenous band: an improved technique for use in the diagnosis of collagenous colitis
Authors: FO Dakhil, FM Stevens
Journal: Endoscopy (2006)

Aims: Collagenous colitis (CC) is underdiagnosed and causes chronic diarrhoea in the elderly; it is characterised by a thick CB (>10m). We undertook this study to determine if the newly described technique, examination of H&E sections under fluorescent light (FH&E) is superior to routine methods for measuring the subepithelial collagen band (CB) depth.
Low estrogen receptor (ER) positive breast cancer and neoadjuvant systemic therapy (NAT): Is response similar to ER+ or to ER- disease?
Authors: Alessandra Landmann, Daniel J. Farrugia, Emilia Diego, Atilla Soran, Ronald Johnson, Marguerite Bonaventura, David J. Dabbs, Beth Clark, Adam Brufsky, Nancy E. Davidson, Barry C. Lembersky, Rachel Catherine Jankowitz, Shannon Puhalla, Gretchen M. Ahrendt, Priscilla F. McAuliffe, Rohit Bhargava
Journal: Journal of Clinical Oncology (2016)

580 Background: ER expression can be semi-quantitatively measured using a Histochemical or H-score that can range from 0 (negative) to 300 (diffuse strong positive).. We sought to demonstrate a difference in pathologic complete response (pCR) rates after NAT between strongly positive and weakly positive ER+ breast cancers. Methods: Retrospective chart review was conducted of patients diagnosed with invasive breast cancer who received NAT from 2010-2014 at our institution. Case inclusion required at least tumor ER status, HER2 status and pCR information. Low ER+ tumors were defined as tumors with ER H-score of 1-100 and their overall pCR rate was compared to that of ER negative (H-score 0), moderate ER+ (H-score 101-200) and high ER+ tumors (H-score 201-300). The data was further analyzed with respect to HER2 status. HER2 results were classified using the 2013 ASCO/CAP HER2 guidelines criteria. HER2 equivocal cases were excluded for this analysis due to small numbers. Univariate analyses were performed using Fisher exact test. All reported p-values are 2 tailed. Results: Of 595 cases, ER H-score information was available on 580 cases. The pCR rate of ER-, low ER+, moderate ER+, high ER+ tumors was 35.6% (78 of 219), 36.3% (29 of 80), 20% (18 of 90), and 9.4% (18 of 191) respectively, and decreased with increasing ER H-score. The pCR rate of low ER+ tumors was similar to that of ER- tumors (p = 1.0) and significantly different from moderate (p = 0.0251) and high ER+ tumors (p < 0.0001). On subset analysis for HER2 status, pCR rate again increased with lower ER H-score in a statistically significant manner in HER2- tumors but not in the HER2+ subset, presumably due to small numbers and the efficacy of modern anti-HER2 therapy that renders ER status less relevant. Conclusions: The pCR rate of low ER+ tumors is similar to ER- tumors. In HER2- tumors, ER H-score is an important determinant of response to NAT. ER status HER2 status pCR (%) p-value (comparison with low ER+ and HER2 matched tumors) Low ER+ - 14/39 (35.9%) NA Mod ER+ - 3/43 (7%) 0.0021 Strong ER+ - 6/128 (4.7%) < 0.0001 ER - - 38/137 (27.7%) 0.3272 Low ER+ + 14/39 (35.9%) NA Mod ER+ + 13/39 (33.3%) 1.0 Strong ER+ + 12/49 (24.5%) 0.3470 ER - + 40/78 (51.3%) 0.1682
Apport de la tomodensitométrie abdominale pour le diagnostic d'appendicite aiguë aux urgences
Authors: JM Catheline, P Wind, G Tincani, M Perez, E Maissiat, P Hoang, J Bénichou
Journal: Endoscopy (2006)

Evaluer l'apport de la tomodensitométrie abdominale (TDM) systématique pour le diagnostic d'appendicite aiguë dans un service d'urgences hospitalier.
Preventive Pediatrics in Medical Education: I. Child Health and Organization of Preventive Pediatrics in Canada
Authors: J H READ
Journal: JAMA (1963)

Any appraisal of child health in Canada must contend with broad cultural and geographical differences reflected in variations in demological and sociological data. However, the data presently available suggest the following trends: (1) Infant and neonatal mortality decreases with the improved facilities of urbanization, but many psycho-social variables need evaluation. (2) Developmental and behavioural problems are the chief areas of parental concern relative to the preschool and adolescent child. (3) Handicapped children require a highly integrated complex of community services of habilitation and rehabilitation. (4) Programs in accident prevention are feasible.
Simplified CYP2D6 metabolizer phenotype categorization of patients treated with tamoxifen: Role for endoxifen level monitoring?
Authors: Clara Inkyung Lee, Amanda Siew Kee Low, Peter Fox, Bavanthi Balakrishnar, Rosemary L Balleine, Bo Gao, Pamela Provan, Sally Coulter, Christopher Liddle, Rina Hui, Nicholas Wilcken, Mark Wong, Howard Gurney
Journal: Journal of Clinical Oncology (2016)

536 Background: Classifications for CYP2D6 phenotypes are established for debrisoquine, sparteine and codeine, but not for tamoxifen. CYP2D6 protein activity can be inferred from the ratio of N-desmethyl-tamoxifen (NDMT) to endoxifen (EDF). CYP2D6polymorphisms are common and can affect CYP2D6 protein activity and EDF level. Retrospective analyses of two breast cancer studies indicate that EDF levels below 15nM may relate to worse outcome. Methods: A target NDMT/EDF ratio was defined as that which was associated with an EDF level of 15nM in 108 Australian tamoxifen-treated patients (pts), dichotomizing the group into ‘Normal’ (NM) and ‘Slow’ CYP2D6 metabolizer groups (SM). Pts were classified according to genotype based on Crews et al Clin Pharmacol Ther 95, 376, 2014 (ultrarapid/extensive, intermediate or poor metabolizers; UM/EM, IM, PM) or a simplified system based on whether anyvariant allele was present. The following alleles were measured: *2, *3, *4, *5, *6, *8, *9, *10, *14, *17, *39, *41, 1N and 2N on germline DNA. Concomitant CYP2D6 inhibitor use was excluded. Results: A target NDMT/EDF ratio of 44 correlated with 15nM EDF level and dichotomized pts into NM (<44; N =90) and SM (>44; N= 18) groups. Association between classification systems and slow metabolizer status is shown in table below. Conclusions: If validated, this simple classification system may be superior to standard systems for predicating slow CYP2D6 metabolism. However, a significant proportion of v/v patients (26%) had normal CYP2D6 activity indicating that CYP2D6 genotype may be a poor measure of protein activity and that direct measurement of endoxifen should be considered. Current genotype classification Simplified classification UM/EM N = 91 IM N = 9 PM N = 8 wt/wt N = 44 wt/v N = 41 v/v N = 23 Slow metabolizer (NDMT/EDF > 44) N = 18 5/91 (5%) 5/9 (56%) 8/8 (100%) 0/44 (0%) 1/41 (2%) 17/23 (74%) Sensitivity 44.4% 94.4% Specificity 100% 93.3% Sensitivity 72.2% Specificity 95.6% v/v pts were further examined but no single allele predicted for SM with many alleles occurring in both SM and NM pts.
Abstract P256: Epigenetic Changes by Nuclear Calcium/Calmodulin-Dependent Protein Kinase II in the Heart
Authors: Coralie Poizat, Gillian Little, Mirko Volkers, Haruhiro Toko, Yan Bai
Journal: Circulation Research (2011)

Calcium is central in the regulation of many cellular functions and alteration of calcium signaling leads to a variety of cardiac disorders. An important question remaining in cardiac biology is how calcium-dependent mechanisms are regulated and more specifically how calcium activates intracellular signaling pathways and regulates gene activity in the cell nucleus. The nuclear isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIB) plays a protective role in the heart under basal conditions, and alteration of its level or activity is associated with pathological events such as cell death and cardiac hypertrophy. We recently made a novel discovery showing that CaMKIIδB couples calcium signals to the genome by targeting specific histones in chromatin. Our preliminary results show that CaMKIIδB selectively phosphorylates histone H3 in vitro and in primary cardiomyocytes. Activation of CaMK activity after α-adrenergic stimulation of primary cardiac cells increases histone H3 phosphorylation at serine 10 (Ser-10), whereas specific elimination of the kinase has the opposite effect. Enhanced phosphorylation of histone H3 Ser-10 is observed in primary fibroblasts and also in primary ventricular myocytes and culminates at 24 hours of stimulation, suggesting that signaling to histone H3 is not limited to highly dividing cells and is not transient. Importantly, Enhanced histone H3 Ser-10 phosphorylation can be detected in the heart of mice subjected to myocardial infarction. These results reveal a new role for CaMK enzymes in chromatin remodeling the heart and that epigenetic changes may contribute to the development cardiac diseases.
Phase II study of gefitinib as first-line chemotherapy in patients with advanced non-small cell lung cancer harboring <i>EGFR</i> mutations and poor prognostic characteristics.
Authors: Shuji Murakami, Saki Manabe, Tetsuro Kondo, Haruhiro Saito, Kouzo Yamada
Journal: Journal of Clinical Oncology (2016)

e20625 Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) are associated with high response rates and significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Owing to their high response rates, EGFR-TKIs could play a decisive role in patients with advanced NSCLC, poor performance status (PS), advanced age, and symptomatic metastasis. Methods: We administered gefitinib to patients with advanced NSCLC harboring EGFR mutations and at least one of the following poor prognostic characteristics: PS 2/3, age ≥ 75 years, massive pleural effusion, symptomatic brain metastasis, symptomatic bone metastasis, and multiple organ metastases. The primary endpoint was the tumor response rate. The secondary endpoints were PFS, OS, and the rates of adverse events. Results: Thirty-seven patients (16 males and 21 females) were enrolled between December 2010 and May 2015. The median age was 74 years (range 42–87 years). One patient had stage IIIB disease, 31 had stage IV disease, and 5 had postoperative recurrence. The numbers of patients with PS 2/3, age ≥ 75 years, massive pleural effusion, symptomatic brain metastasis, symptomatic bone metastasis, and multiple organ metastases were 6, 16, 9, 3, 14, and 22, respectively. The overall response rate was 67.6%. The median PFS and median OS were 9.4 and 18.7 months, respectively. The response rates were generally similar in patients with each poor prognostic characteristic. In multivariable analyses, pleural effusion was independently associated with poor PFS (hazard ratio 3.3; P = 0.027) and poor OS (hazard ratio 4.1; P = 0.040). Interstitial lung disease occurred one patient. There were no treatment-related deaths. Conclusions: he response rates to gefitinib in patients with advanced NSCLC were similarly high among patients with poor PS, advanced age, and symptomatic metastasis. However, patients with pleural effusion had poor PFS and OS. Clinical trial information: 000004822.
Increased risk of acute arterial events in young patients and severely active IBD: a nationwide French cohort study
Authors: Julien Kirchgesner, Laurent Beaugerie, Fabrice Carrat, Nynne Nyboe Andersen, Tine Jess, Michaël Schwarzinger
Journal: Gut (2017)

Objective Magnitude and independent drivers of the risk of acute arterial events in IBD are still unclear. We addressed this question in patients with IBD compared with the general population at a nationwide level. Design Using the French National Hospital Discharge Database from 2008 to 2013, all patients aged 15 years or older and diagnosed with IBD were identified and followed up until 31 December 2013. The rates of incident acute arterial events were calculated and the impact of time with active disease (period around hospitalisation for IBD flare or IBD-related surgery) on the risk was assessed by Cox regression adjusted for traditional cardiovascular risk factors. Results Among 210 162 individuals with IBD (Crohn’s disease (CD), n=97 708; UC, n=112 454), 5554 incident acute arterial events were identified. Both patients with CD and UC had a statistically significant overall increased risk of acute arterial events (standardised incidence ratio (SIR) 1.35; 95% CI 1.30 to 1.41 and SIR 1.10; 95 CI 1.06 to 1.13, respectively). The highest risk was observed in patients under the age of 55 years, both in CD and UC. The 3-month periods before and after IBD-related hospitalisation were associated with an increased risk of acute arterial events in both CD and UC (HR 1.74; 95 CI 1.44 to 2.09 and 1.87; 95% CI 1.58 to 2.22, respectively). Conclusion Patients with IBD are at increased risk of acute arterial events, with the highest risk in young patients. Disease activity may also have an independent impact on the risk.
Variants in the fetal genome near FLT1 are associated with risk of preeclampsia
Authors: Ralph McGinnis, Valgerdur Steinthorsdottir, Nicholas O Williams, Gudmar Thorleifsson, Scott Shooter, Sigrun Hjartardottir, Suzannah Bumpstead, Lilja Stefansdottir, Lucy Hildyard, Jon K Sigurdsson, John P Kemp, Gabriela B Silva, Liv Cecilie V Thomsen, Tiina Jääskeläinen, Eero Kajantie, Sally Chappell, Noor Kalsheker, Ashley Moffett, Susan Hiby, Wai Kwong Lee, Sandosh Padmanabhan, Nigel A B Simpson, Vivien A Dolby, Eleonora Staines-Urias, Stephanie M Engel, Anita Haugan, Lill Trogstad, Gulnara Svyatova, Nodira Zakhidova, Dilbar Najmutdinova, Anna F Dominiczak, Håkon K Gjessing, Juan P Casas, Frank Dudbridge, James J Walker, Fiona Broughton Pipkin, Unnur Thorsteinsdottir, Reynir T Geirsson, Debbie A Lawlor, Ann-Charlotte Iversen, Per Magnus, Hannele Laivuori, Kari Stefansson, Linda Morgan
Journal: Nature Genetics (2017)
Correlation Between Somatic Mutation Burden, Neoantigen Load and Progression Free Survival in Multiple Myeloma: Analysis of MMRF CoMMpass Study
Authors: Amber Miller, Laura Cattaneo, Yan W Asmann, Esteban Braggio, Jonathan J Keats, Daniel Auclair, Sagar Lonial, The MMRF CoMMpass Network, Stephen J. Russell, A. Keith Stewart
Journal: Blood (2016)
Efficacy and safety of eribulin in patients with triple negative metastatic breast cancer: Real life experience.
Authors: Alexey Manikhas, Elena Kovalenko, Valentina Manzyuk, Larisa V Bolotina, Larisa Zhilyaeva, Elena Karabina, Dmitry Ponomarenko
Journal: Journal of Clinical Oncology (2017)

e12580 Background: Eribulin demonstrates improved overall survival compared to standard treatments, Her2-negative and TNBC patients have the most survival benefit. We sought to describe treatment patterns of eribulin and clinical outcomes among TNBC patients with advanced breast cancer treated in community oncology practices across the Russian Federation. Methods: Patients treated with eribulin anytime between January 1, 2014 and January 1, 2017 with a diagnosis of MBC were identified by providers within the Russia Oncology Research Center. Providers reviewed the health records (electronic or paper-based) and abstracted selected data points into an electronic case report form for each eligible patient. Results: A total 52 TNBC patients were considered by 10 providers. A median of age at start of eribulin was 47,5 (39-55) yrs and ECOG status 0-1 were assessed. Most of the pts (92,3%) had visceral mts, a median number metastatic disease regions was 2 (1-3). Eribulin was administered as the 1 st and 2 nd line of BC treatment to 14 (26,9%) pts, 3 rd line – to 9 (17,3%), the 4 th and later lines – to 29 (55,8%) pts. Objective response occurred in 5 (9,6%) pts. Stable disease registered in 24 (46,1%) pts. Median PFS was 3,0 months (95% CI 1,9-8,55). Overall the drug was well tolerated. The most common type of toxicity was hematologic. Neutropenia gr II was observed in 8 (15,4) pts and III-IV gr in 6 (11,5%), two cases of febrile neutropenia were registered. 4 (7,7%) pts experienced fatigue gr II. Peripheral neuropathy gr II was observed in 4 (7,7%) pts. Dose reduction due to toxicity was performed in 8 (15,4%) pts. Treatment was never withdrawn due to toxicity. Conclusions: This is the first real-life study of clinical outcomes, for patients initiating eribulin therapy for TNBC in community oncology practices throughout the Russian Federation. . Our experience with Eribulin in TNBC patients confirms it efficacy and safety in all lines of treatment, including intensively pretreated patients in this hard-to-treat population.
Abstract 376: A Potential Role for TRAIL in the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Allan Lawrie, Mark Southwood, Jay Suntharalingam, Sheila E Francis, David C Crossman, Nicholas W Morrell, Christopher M Newman
Journal: Circulation (2007)

Pulmonary arterial hypertension (PAH) is a life threatening disease characterised by the narrowing and occlusion of small pulmonary arteries. Endothelial cell (EC) loss, and increased proliferation and migration of pulmonary artery smooth muscle cells (PA-SMC) are strongly implicated in disease pathogenesis. Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) induces EC apoptosis and SMC migration, consistent with an important role in vascular biology. TRAIL is a type II TNF family transmembrane protein, whose extracellular domain can be proteolytically cleaved from the cell surface to act as a soluble cytokine (sTRAIL) capable of binding to five TRAIL receptors, (TRAIL-R1– 4) and osteoprotegerin (OPG). We hypothesised that TRAIL expression is increased in PAH and that this contributes to the excessive migration of PA-SMC that characterises this condition. TRAIL gene expression was studied in microarrays of PA-SMC RNA isolated from idiopathic PAH (IPAH) patients, and from the lungs of monocrotaline-treated (Mct) rats. Immunohistochemistry was performed to localise TRAIL in both human and rat lung sections. To investigate the functional effects of TRAIL in PA-SMC, human PA-SMC were incubated with recombinant human TRAIL (1–50 ng/ml) for 5h and migration assessed by transwell assay. TRAIL gene expression was 10-fold higher in PA-SMC from IPAH patients compared to controls. Moreover, strong TRAIL immunoreactivity was observed in pulmonary vascular lesions from IPAH patients but not in vessels from patients undergoing lobectomy for lung carcinoma. In the Mct-rat model of PAH we found a 20-fold increase in TRAIL gene expression and a 2-fold increase in protein from whole lung extracts. Immunohistochemistry revealed strong TRAIL immunoreactivity within the muscularised pulmonary arteries of Mct-treated but not saline-treated control rats. Recombinant TRAIL was found to induce a dose dependent (maximum 3 fold) increase in migration of human PA-SMC compared with cells incubated with 0.1% serum alone. These data suggest that TRAIL may be an important molecule in the pathogenesis of PAH. Further studies to elucidate the regulation and function of this molecule in PAH are warranted.
Neuroblastoma is composed of two super-enhancer-associated differentiation states
Authors: Tim van Groningen, Jan Koster, Linda J Valentijn, Danny A Zwijnenburg, Nurdan Akogul, Nancy E Hasselt, Marloes Broekmans, Franciska Haneveld, Natalia E Nowakowska, Johannes Bras, Carel J M van Noesel, Aldo Jongejan, Antoine H van Kampen, Linda Koster, Frank Baas, Lianne van Dijk-Kerkhoven, Margriet Huizer-Smit, Maria C Lecca, Alvin Chan, Arjan Lakeman, Piet Molenaar, Richard Volckmann, Ellen M Westerhout, Mohamed Hamdi, Peter G van Sluis, Marli E Ebus, Jan J Molenaar, Godelieve A Tytgat, Bart A Westerman, Johan van Nes, Rogier Versteeg
Journal: Nature Genetics (2017)
Predicting risk of undiagnosed COPD: development and validation of the TargetCOPD score
Authors: Shamil Haroon, Peymane Adab, Richard D. Riley, David Fitzmaurice, Rachel E. Jordan
Journal: European Respiratory Journal (2017)

Chronic obstructive pulmonary disease (COPD) is greatly underdiagnosed worldwide and more efficient methods of case-finding are required. We developed and externally validated a risk score to identify undiagnosed COPD using primary care records. We conducted a retrospective cohort analysis of a pragmatic cluster randomised controlled case-finding trial in the West Midlands, UK. Participants aged 40–79 years with no prior diagnosis of COPD received a postal or opportunistic screening questionnaire. Those reporting chronic respiratory symptoms were assessed with spirometry. COPD was defined as presence of relevant symptoms with a post-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio below the lower limit of normal. A risk score was developed using logistic regression with variables available from electronic health records for 2398 participants who returned a postal questionnaire. This was externally validated among 1097 participants who returned an opportunistic questionnaire to derive the c-statistic, and the sensitivity and specificity of cut-points. A risk score containing age, smoking status, dyspnoea, prescriptions of salbutamol and prescriptions of antibiotics discriminated between patients with and without undiagnosed COPD (c-statistic 0.74, 95% CI 0.68–0.80). A cut-point of ≥7.5% predicted risk had a sensitivity of 68.8% (95% CI 57.3–78.9%) and a specificity of 68.8% (95% CI 65.8.1–71.6%). A novel risk score using routine data from primary care electronic health records can identify patients at high risk for undiagnosed symptomatic COPD. This score could be integrated with clinical information systems to help primary care clinicians target patients for case-finding.