tbuckley/cabot-search huggingface dataset:
Bridging the quality chasm in maternal, newborn, and child healthcare in low- and middle-income countries
Authors: Lars Åke Persson
Journal: PLoS Medicine (2017)

At the end of the Millennium Development Goal era, extreme poverty had been halved, and mortality in children below 5 years of age had been reduced from 90 per 1,000 live births in 1990 to 43 per 1,000 in 2015 [1].This decrease in child deaths was the result of concerted global efforts to increase the coverage of evidence-based interventions [2].Emphasis was primarily given to post-neonatal, child, and maternal deaths.Neonatal survival was added to the agenda after a few years [3], as was equity in child survival between and within countries [4].The Sustainable Development Goals include targets for maternal, newborn, and child health under the umbrella of universal health coverage by 2030, where the quality of care and health equity are fundamental components [5].These targets are aligned with global action plans to end preventable maternal mortality and save neonatal lives.In some countries, the rapid shift towards facility-based deliveries has increased neonatal mortality [6,7].These unexpected results are most likely due to a poor quality of services provided.To improve maternal and neonatal survival, quality of care must be strengthened when facility-based deliveries increase [8]. What is quality of care?WHO describes quality of care, as "the extent to which healthcare services provided to individuals and patient populations improved desired outcomes.In order to achieve this, healthcare must be safe, effective, timely, efficient, equitable, and people-centred" [9].Three decades ago Avedis Donabedian developed a conceptual framework in which quality of care was classified under 3 categories: structure (material and human resources and organizational structure), process (giving and receiving care), and outcome (effects on health status) [10].This week in PLOS Medicine, Hannah Leslie and colleagues show that the facility infrastructure was poorly associated with the process, that is, the clinical quality of care provided to patients [11].This cross-sectional assessment was based on 4,300 facilities in Haiti, Kenya, Malawi, Namibia, Rwanda, Senegal, Tanzania, and Uganda between 2007 and 2015.A wellequipped facility could provide inadequate care, and a facility scoring low on readiness could deliver care of good quality.This finding does not imply that service readiness is unimportant; equipment is always required to measure an expectant mother's blood pressure.The analyses did not manage to demonstrate a minimum threshold of facility infrastructure needed for the provision of good care.The cross-sectional design of the study may be a limitation, as it does not capture the dynamics of the structural readiness over time.There may also be issues related to range and validity of available data on input and process.Still, the paper shows that the
CNS Endothelial Cell Activation Emerges as a Driver of CAR T Cell–Associated Neurotoxicity
Authors: Crystal L. Mackall, David B. Miklos
Journal: Cancer Discovery (2017)

Abstract Summary: Central nervous system (CNS) toxicity associated with chimeric antigen receptor–based therapeutics has emerged as a significant cause of morbidity and mortality, and insights into the pathophysiology of this syndrome have been lacking. A new study provides evidence that cytokine-induced CNS endothelial cell activation leading to disruption of the blood–brain barrier plays an early and critical role in this phenomenon. These insights provide new opportunities for targeted therapeutic interventions to modulate endothelial cell activation. Cancer Discov; 7(12); 1371–3. ©2017 AACR. See related article by Gust et al., p. 1404.
Abstract 19715: Automated External Defibrillation for the MRI Environment Enables Imaging and Interventions in Higher Risk Patients
Authors: Ehud J Schmidt, Ronald D Watkins, Menehem M Zviman, Michael A Guttman, Wei Wang, Henry H Halperin
Journal: Circulation (2016)

Background: MRI Imaging or MRI-guided interventions of higher-risk patients requires detecting and treating acute cardiac events inside the MRI environment, since current practice of removing the p...
Assessment of child or young person with a possible eating disorder
Authors: Helen Bould, Claudia Newbegin, Mina Fazel, Anne Stewart, Alan Stein
Journal: BMJ (2017)

### What you need to know

A mother presents to discuss her 13 year old daughter’s changed eating patterns. The daughter is involved in a lot of sport at school and is running cross country for the county, but is no longer eating properly and seems withdrawn. The daughter appears to be losing weight, but she does not want to be weighed and alludes to thinking she is fat. She doesn’t know her mother has come to see you; the mother wants to know what she can do without you seeing her daughter, as she is worried her daughter will become upset and withdrawn if others are involved.

Assessing young people with possible eating disorders can be complex for a variety of reasons. Building a therapeutic relationship with a young person with a possible eating disorder and their family is key to enabling a thorough assessment and ongoing management, but it introduces difficult issues regarding confidentiality and risk. This Practice Pointer is aimed at non-specialist doctors and will offer advice on building therapeutic relationships in consultation with a child or young person, and with their parent(s), what information to gather, and how to do so sensitively, and the role of the parent or carer in treatment. We recommend that it is read alongside the accompanying Clinical Update for the evidence base and detailed notes on examination, investigations, when to refer, and risk. The advice in this Practice Pointer is based on expert experience.

### An approach to a young person and parent/carer presenting together

### Sensitive information gathering

The most …
Abstract 12257: Calmodulin Interacting Genes as a Novel Candidate for Pathogenesis of Long-QT Syndrome
Authors: Takeshi Aiba, Daichi Shigemizu, Hidewaki Nakagawa, Kouichi Ozaki, Fuyuki Miya, Wataru Satake, Tatsushi Toda, Yoshihiro Miyamoto, Akihiro Fujimoto, Yutaka Suzuki, Michiaki Kubo, Tatsuhiko Tsunoda, Kengo Kusano, Satoshi Yasuda, Hisao Ogawa, Toshihiro Tanaka, Wataru Shimizu
Journal: Circulation (2015)

Background: Approximately 30% of long-QT syndrome (LQTS) cases remains genetically elusive. Here, we investigated usefulness of the whole exon sequencing (WES) by next-generation sequencing for identification of novel pathogenic candidates which directly or indirectly interact with proteins encoded by known LQTS genes. Methods: Of 1815 Japanese LQTS cohort patients, WES was performed in 59 LQTS patients and 61 unaffected individuals from 35 families and 138 unrelated LQTS cases, all were screened major LQTS genes such as KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2 and KCNJ2. After WES, the genes known as inherited arrhythmias were screened by the Human Gene Mutation Database, and the Sanger sequencing was also referred for validation of the mutations and common variants were excluded by the public (1000G, ESP6500 and dbSNP) and Riken database. Results: Total 92 candidate mutations including 11 de novo, 5 recessive (2 homozygous and 3 compound heterozygous) and 73 dominant mutations in 88 genes were identified in 23 of the 35 families. Protein-protein interaction network analyses revealed ten new pathogenic candidates (WDR26, RYR2, UBR5, UBR4, KIF21B, CIT, SIRT6, PIK3CG, PI4KA and RIMS1) that directly or indirectly interact with proteins encoded by known LQTS genes. Furthermore, gene based association studies identified an additional novel candidate; SLC2A5. Taken together, mutations in these new candidates or known LQTS genes were identified in 13 of the 35(37%) genotype-unknown LQTS families. Moreover, 5 of the 11 newly identified candidates directly interact with calmodulin (CaM). Subsequent variant analysis in the independent set of 138 cases identified 16 variants in the 11 genes, of which, 14 (87.5%) were in the CaM-interacting genes and 8 of them were in RYR2. Many of the patients with RyR2 mutation had similar exercise-induced cardiac events (3 syncope, 2 VF) as LQTS patients, while the QTc interval was shorter in patients with RyR2 mutation than those with genotype-negative LQTS (441±32 vs. 487±47ms; p=0.01). Conclusions: These findings suggest that CaM interacting genes have an important role on the pathogenesis of LQTS. In particular, RYR2 mutations may cause an overlap syndrome between catecholaminergic polymorphic ventricular tachycardia and LQTS.
CRISPR/Cas9-edited NSG mice as PDX models of human leukemia to address the role of niche-derived SPARC
Authors: I Tirado-Gonzalez, E Czlonka, A Nevmerzhitskaya, D Soetopo, E Bergonzani, A Mahmoud, A Contreras, I Jeremias, U Platzbecker, J P Bourquin, U Kloz, F Van der Hoeven, H Medyouf
Journal: Leukemia (2017)

CRISPR/Cas9 edited  NSG  mice as PDX models of human leukemia to address the role of niche-derived SPARC
An ALOX12–12-HETE–GPR31 signaling axis is a key mediator of hepatic ischemia–reperfusion injury
Authors: Xiao-Jing Zhang, Xu Cheng, Zhen-Zhen Yan, Jing Fang, Xiaozhan Wang, Weijun Wang, Zhen-Yu Liu, Li-Jun Shen, Peng Zhang, Pi-Xiao Wang, Rufang Liao, Yan-Xiao Ji, Jun-Yong Wang, Song Tian, Xue-Yong Zhu, Yan Zhang, Rui-Feng Tian, Lin Wang, Xin-Liang Ma, Zan Huang, Zhi-Gang She, Hongliang Li
Journal: Nature Medicine (2017)
Abstract 13: Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients
Authors: Ashleigh Porter, Gregory A. Daniels, Sandip Pravin Patel, Assuntina Sacco, Kimberly C. Banks, Ezra E. W. Cohen
Journal: Clinical Cancer Research (2017)

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is an increasingly prevalent disease but effective targeted therapy is lacking. The use of next generation sequencing (NGS) in the identification of novel targets has been suggested as a way to potentially expand therapeutic options and thereby improve outcomes. Methods: Data were collected on patients with recurrent and metastatic (R/M) head and neck cancers who underwent molecular profiling of blood samples utilizing Guardant360, a 70-gene circulating tumor DNA (ctDNA) NGS platform. CtDNA sequencing data was compared to tumor NGS data, when available. Best response to therapy was assessed using RECIST measures. Results: 60 HNSCC patients were evaluated from February 2015 to June 2016. The most common tumor type and histology was oropharyngeal squamous cell carcinoma (n=21), which was commonly human papillomavirus (HPV) positive (n=15). Other cancer types included salivary gland and thyroid cancers. The most common mutations identified by ctDNA analysis were TP53 (98%), PIK3CA (43%), NOTCH1 (38%), and ARID1A (36%). These findings were consistent with results from tumor sequencing data (n=29) where TP53 (48%) and PIK3CA (24%) were also reported with the highest frequency. Importantly, 73% (n=22) of patients had alterations identified in ctDNA that were not present in tumor specimens. Actionable mutations were identified in 66% of HNSCC and in 50% salivary gland cancer patients. Of patients with actionable mutations, 10% (n=6) received matched targeted therapy (MTT): 3 (50%) had stable disease (SD), 1 had progressive disease (PD), and 2 were not evaluated. Of those who did not receive targeted therapy (n=23), 1 (4.3%) patient had a complete response treated with immunotherapy, 11 (47%) had SD, and 11 (47%) had PD. Conclusions: Analysis of ctDNA may play a role in management decisions in R/M HNSCC. The majority of patients had unique mutations identified on ctDNA. The utility of ctDNA NGS and its role in patient management should be explored in future studies. Citation Format: Ashleigh Porter, Gregory A. Daniels, Sandip Pravin Patel, Assuntina Sacco, Kimberly C. Banks, Ezra E. W. Cohen. Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 13.
Abstract 13094: High Glucose/High Lipids Impair Vascular Adiponectin Function via Inhibition of Caveolin-1/AdipoR1 Signalsome Formation
Authors: Yue Chen, Wayne Lau, Theodore Christopher, Bernard Lopez, Xin Ma, Yajing Wang
Journal: Circulation (2015)

Background and Aims: Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Methods and Results: In HUVECs cultured under normal condition (control), APN caused eNOS, AMPK and Akt phosphorylation, increased nitric oxide (NO) production, and inhibited TNF-induced adhesion molecule expression. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P&lt;0.01 vs. control), and APN’s anti-TNFα effect was blunted (P&lt;0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P&lt;0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN’s anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced, and the vasorelaxative response to APN was impaired in vascular segments from diabetic animals. Conclusion: The current study demonstrates for the first time that the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.
Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells
Authors: Katharina Essig, Desheng Hu, Joao C. Guimaraes, Dominik Alterauge, Stephanie Edelmann, Timsse Raj, Jan Kranich, Gesine Behrens, Alexander Heiseke, Stefan Floess, Juliane Klein, Andreas Maiser, Susan Marschall, Martin Hrabĕ de Angelis, Heinrich Leonhardt, Cornelis F. Calkhoven, Elfriede Noessner, Thomas Brocker, Jochen Huehn, Anne B. Krug, Mihaela Zavolan, Dirk Baumjohann, Vigo Heissmeyer
Journal: Immunity (2017)
Abstract P321: Insulin Resistance is Associated with Incident Coronary Heart Disease but Not Stroke Among African Americans: The Jackson Heart Study
Authors: Valery S Effoe, Lynne E Wagenknecht, Justin B Echouffo-Tcheugui, Haiying Chen, Joshua J Joseph, Rita R Kalyani, Ronny A Bell, Wen-Chih H Wu, Ramon Casanova, Alain G Bertoni
Journal: Circulation (2016)

Background: The association between the homeostasis model assessment for insulin resistance (HOMA-IR) and CVD varies by race/ethnicity and is often non-existent or weaker in African Americans (AAs). Triglyceride levels (110-149 mg/dl) below the current metabolic syndrome threshold are associated with insulin resistance in AAs, suggesting that the McAuley index (MA index ), based on insulin and triglycerides, may predict CHD and stroke better than HOMA-IR. We investigated this association in the Jackson Heart Study, a large longitudinal cohort of AAs. Methods: Insulin resistance was estimated for 3565 participants without diabetes and CVD at baseline using the MA index (exp [2.63-0.28 In(insulin in mU/l) - 0.31 In(triglycerides in mmol/l)]) and its association with incident CHD and stroke (composite outcome) was compared against that of the HOMA-IR index. A lower MA index and higher HOMA-IR are indicative of insulin resistance. Cox regression analysis was used to estimate adjusted hazard ratios (HR) for incident CHD and stroke, individually and as a composite. Results: There were 158 events (89 CHD-only, 58 stroke-only, and 11 CHD/stroke) over a median follow-up of 8.4 years. After adjustment for demographic factors, the risk of the composite outcome decreased with each SD increase in the MA index (HR 0.80; 95% CI: 0.67 - 0.96), with no attenuation following further control for CHD and stroke risk factors. When considered individually, the MA index was associated with CHD (HR 0.71, 95% CI: 0.55 - 0.92), but not stroke (HR 0.96, 95% CI: 0.74 - 1.25) risk. The log(HOMA-IR)-CHD association was comparable to that observed with the MA index (Table 1). For both indices, an association was present in men, but not in women (P interaction = 0.01 and 0.2 for log(HOMA-IR) and MA index , respectively). Conclusions: The performance of the MA index in predicting CHD and stroke risk in AAs is comparable to the widely used HOMA-IR index. Our findings suggest a role of insulin resistance in CHD but not stroke risk in this population.
Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kδ in Mature B-cell Malignancies
Authors: Jeffrey D. Cooney, An-Ping Lin, Daifeng Jiang, Long Wang, Avvaru N. Suhasini, Jamie Myers, ZhiJun Qiu, Albert Wölfler, Heinz Sill, Ricardo C.T. Aguiar
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kδ. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted. Clin Cancer Res; 24(5); 1103–13. ©2017 AACR.
Geltamo-IPI Distinctly Identifies a Very High Risk Group in Difuse Large B-Cell Lymphoma (DLBCL) of Non B-Germinal-Center Origin Treated with Chemo-Immunotherapy
Authors: Carlos Montalban, Antonio Diaz-Lopez, Alejandro Martín, Monica Baile, Jose M. Sanchez, Juan-Manuel Sancho, Olga García, Silvana Novelli, Ana Monter Rovira, Antonio Salar, Mariana Bastos, Antonio Gutierrez, Raul Cordoba, Teresa Arquero, Sonia González de Villambrosia, Gilberto Barranco, Raquel de Oña, Azueg Hong, Maria Casanova, Armando Lopez-Guillermo, Maria J. Rodriguez-Salazar, Juan F. Dominguez, Ruben Fernandez, Jose Antonio Queizan, Jose Rodriguez, Victor Abraira, Juan F. Garcia
Journal: Blood (2017)
Meta-Analyses of Therapies for Postmenopausal Osteoporosis
Authors: Ann Cranney, Peter Tugwell, George Wells, Gordon Guyatt
Journal: Endocrine Reviews (2002)

The availability of new therapeutic agents has made clinical decision-making in osteoporosis more complex. Because individual clinicians cannot systematically collect and assimilate all the evidence bearing on the efficacy of osteoporosis therapies, they require summaries for evidence-based decision-making. Systematic reviews using rigorous methods provide an unbiased, comprehensive summary of the available evidence, and meta-analysis provides the most precise possible estimate of the treatment effect. The articles in this series represent systematic reviews of a number of osteoporosis therapies: calcium and vitamin D, the bisphosphonates alendronate and risedronate, hormone replacement therapy, raloxifene, and calcitonin. We used state-of-the-art methodology to provide the most clear and accurate characterization of the effectiveness of these therapies. These include explicit eligibility criteria; a comprehensive search; validity assessment that focused on concealment of randomization, blinding, and completeness of follow-up; and sophisticated analytic methods. In addition, two or more reviewers made independent, reproducible decisions regarding study inclusion and assessments of study validity. Only alendronate and risedronate reduced the risk of both nonvertebral and vertebral fractures. Other agents that reduced vertebral fracture included raloxifene, etidronate, vitamin D, and calcitonin. Clinicians should consider these results when selecting antiosteoporosis therapies for postmenopausal women.