tbuckley/cabot-search huggingface dataset:
Implementation of an Integrated Approach to the National HIV/AIDS Strategy for Improving Human Immunodeficiency Virus Care for Youths
Authors: J. Dennis Fortenberry, Linda J. Koenig, Bill G. Kapogiannis, Carrie L. Jeffries, Jonathan M. Ellen, Craig M. Wilson
Journal: JAMA Pediatrics (2017)

Youths aged 13 to 24 years old living with human immunodeficiency virus (HIV) are less likely than adults to receive the health and prevention benefits of HIV treatments, with only a small proportion having achieved sustained viral suppression. These age-related disparities in HIV continuum of care are owing in part to the unique developmental issues of adolescents and young adults as well as the complexity and fragmentation of HIV care and related services. This article summarizes a national, multiagency, and multilevel approach to HIV care for newly diagnosed youths designed to bridge some of these fragmentations by addressing National HIV/AIDS Strategy goals for people living with HIV.Three federal agencies developed memoranda of understanding to sequentially implement 3 protocols addressing key National HIV/AIDS Strategy goals. The goals were addressed in the Adolescent Trials Network, with protocols implemented in 12 to 15 sites across the United States. Outcome data were collected from recently diagnosed youth referred to the program.Cross-agency collaboration, youth-friendly linkage to care services, community mobilization to address structural barriers to care, cooperation among services, proportion of all men who have sex with men who tested, and rates of linkage to prevention services.The program addressed National HIV/AIDS Strategy goals 2 through 4 including steps within each goal. A total of 3986 HIV-positive youths were referred for care, with more than 75% linked to care within 6 weeks of referral, with almost 90% of those youths engaged in subsequent HIV care. Community mobilization efforts implemented and completed structural change objectives to address local barriers to care. Age and racial/ethnic group disparities were addressed through targeted training for culturally competent, youth-friendly care, and intensive motivational interviewing training.A national program to address the National HIV/AIDS Strategy specifically for youths can improve coordination of federal resources as well as implement best-practice models that are adapted to decrease service fragmentation and systemic barriers at local jurisdictions.
Recognition of early mortality in multiple myeloma by a prediction matrix
Authors: Howard Terebelo, Shankar Srinivasan, Mohit Narang, Rafat Abonour, Cristina Gasparetto, Kathleen Toomey, James W. Hardin, Gail Larkins, Amani Kitali, Robert M. Rifkin, Jatin J. Shah
Journal: American Journal of Hematology (2017)

Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%-14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r-ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma-specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow-up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ-5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient-specific treatment strategies to improve outcomes.
Scientific Advances in Thoracic Oncology 2016
Authors: Ross A. Soo, Emily C.A. Stone, K. Michael Cummings, James R. Jett, John K. Field, Harry J.M. Groen, James L. Mulshine, Yasushi Yatabe, Lukas Bubendorf, Sanja Dacic, Ramon Rami-Porta, Frank C. Detterbeck, Eric Lim, Hisao Asamura, Jessica Donington, Heather A. Wakelee, Yi-Long Wu, Kristin Higgins, Suresh Senan, Benjamin Solomon, Dong-Wan Kim, Melissa Johnson, James C.H. Yang, Lecia V. Sequist, Alice T. Shaw, Myung-Ju Ahn, Daniel B. Costa, Jyoti D. Patel, Leora Horn, Scott Gettinger, Solange Peters, Murry W. Wynes, Corinne Faivre-Finn, Charles M. Rudin, Anne Tsao, Paul Baas, Ronan J. Kelly, Natasha B. Leighl, Giorgio V. Scagliotti, David R. Gandara, Fred R. Hirsch, David R. Spigel
Journal: Journal of Thoracic Oncology (2017)
Stability of the scat3 and association with game day head impacts in non-concussed amateur australian rules football players
Authors: Catherine Wilmott, Andrew S McIntosh, Teresa Howard, Biswadev Mitra, Bleydy Dimech-Betancourt, Jeffrey V Rosenfeld
Journal: British Journal of Sports Medicine (2017)

Objective This pilot study investigated SCAT3 from baseline to post-game among non-concussed amateur Australian Rules footballers, and association with game day head impacts. Design Peak linear acceleration (PLA) of the head (&gt;10 g ) was measured by wearable impact sensor X2Biosytems xPatch. SCAT3 was administered at baseline and post-game. Participants Amateur Australian Rules footballers n=68. Main results Common symptoms at baseline: fatigue, trouble falling asleep &amp; neck pain. N=57 sustained 2088 impacts&gt;10 g (Mean PLA=14.40 g , range 10–115.78 g ). Measured PLA among males (M=15.11 g , SD 3.51) and females (M=16.60 g , SD 4.04), U=288.00, z=−1.24, p=0.217 did not differ, however, males (M=46.13, SD=50.4) sustained significantly more impacts than females (M=17.63, SD=13.20), U=214.00, z=−2.46, p=0.013. Greater symptom severity was found post-game (M=6.16, SD=8.17) compared to baseline (M=4.04, SD=6.34), z=−0.32, p=0.001, along with greater symptom total (p=0.011). Those with higher mean PLA demonstrated slower tandem gait. A similar pattern of SCAT change was observed for the No Impact group, and there were no significant group differences in SCAT change scores. Conclusions Consistent with previous findings players were not asymptomatic at baseline. Increase in symptom severity post-game was generally independent of head impact. Furthermore, the lack of association between PLA and SCAT3 change scores in this non-concussed Impact group suggests that other factors may contribute to such changes. Competing interests None.
Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in <i>RAS</i> mutant cancers
Authors: Chaoyang Sun, Yong Fang, Jun Yin, Jian Chen, Zhenlin Ju, Dong Zhang, Xiaohua Chen, Christopher P. Vellano, Kang Jin Jeong, Patrick Kwok-Shing Ng, Agda Karina B. Eterovic, Neil H. Bhola, Yiling Lu, Shannon N. Westin, Jennifer R. Grandis, Shiaw-Yih Lin, Kenneth L. Scott, Guang Peng, Joan Brugge, Gordon B. Mills
Journal: Science Translational Medicine (2017)

Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor–induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.
Validation of the kinarm end-point robot for clinical assessment of acute sport concussion sensory, motor, and neurocognitive impairment in athletes
Authors: Benson Brian W, Cosh Madeline, Mang Cameron S, Stephen H. Scott, Debert Chantel, Dukelow Sean
Journal: British Journal of Sports Medicine (2017)

Objective To determine if there is a significant association between KINARM robotic sensorimotor and neurocognitive measurements at baseline, ≤10 days post-concussion (IPC), and when clinically asymptomatic (CA). Design Double-blind, prospective case series. Setting Four athletic seasons (2011–2015). Participants 1,214 elite athletes (904 males, 310 females, mean age: 18 and 20 years, respectively). Outcome measures Fifty-seven parameters from five robotic tasks (Visually Guided Reaching (VGR), Position Matching (PM), Object Hit, Object Hit and Avoid, Trail Making B (TMB)) characterising sensorimotor and neurocognitive function. Linear regression was used to determine if there was a significant association between baseline, IPC, and CA measurements, adjusting for potential predictors (age, sex, concussion history, recurrent concussion during study, number of baseline assessments, method (seated versus standing), Post-Concussion Symptom Scale Score (PCSS), days post-concussion at testing) and learning effect. Main results 95 athletes sustained 102 concussions. There was a clear reduction in performance in concussed athletes on individual parameters compared to non-concussed repeat performance. Significant predictors of impairment were: 1) higher PCSS for VGR (IPC): Reaction Time (p&lt;0.001), Min-Max Speed Difference (m/s) (p=0.001), Path Length Ratio (p=0.001), and TMB (CA): Test Time (p=0.003), Dwell Time (p=0.003); 2) older athletes for VGR (IPC): Speed Maxima Count (p&lt;0.01); 3) less days post-concussion at IPC testing for PM Contraction/Expansion Ratio XY (p=0.005); and 4) recurrent concussion during study period for non-dominant PM Shift Y (p=0.005). Conclusions Results of this large prospective study suggest the KINARM robot is a valid, objective tool for quantifying sensorimotor and neurocognitive impairment in concussed athletes. Competing interests Brian W Benson In the future may receive a small royalty from BKIN Technologies Ltd. in consideration for assisting with development and validation of the KINARM end-point robotic device for use in acute sport concussion assessment and management. None. Co-founder and CSO of BKIN Technologies that commercialises the KINARM robot.
HGG-12. HYPOXIA SEEMS TO BE FREQUENTLY UPREGULATED IN THE PEDIATRIC HIGH GRADE GLIOMA AND DIPG
Authors: Anne-Florence Blandin, Aurelie Durand, Marie Litzler, Eric Guerin, Izzie Jacques Namer, Dominique Guenot, Natacha Entz-Werle
Journal: Neuro-Oncology (2017)

Pediatric high grade glioma (pHGGs), including sus-tentorial and DIPG, are known to have a very dismal prognosis. For instance, even an increased knowledge on molecular biology driving this brain tumor entity, there is no treatment able to cure those patients. Therefore, we were focusing on a translational pathway able to increase the cell resistance to treatment and to reprogram metabolically tumor cells, which are, then, adapting easily to a hypoxic microenvironment. We, previously, observed that the resistance to mTor and HIF1 inhibitions was completely linked to HIF2 hyperexpression spontaneously in the pHGG and DIPG cell lines. To establish, the crucial role of the hypoxic pathways in pHGG tumors themselves, we assessed their protein and transcriptomic deregulations in a pediatric cohort of pHGGs, as well as the metabolomic status. We tested 28 patients and could isolate 4 types of tumor profiles with immunohistochemical analyses. The first one was defined by the absence of HIF/HIF2 expression (6 tumors), the second one was just overexpressing HIF1 (9 tumors), the third one is the smaller with an isolated HIF2 hyperexpression (3 cases) and the last one where HIF1 and HIF2 and concomitantly expressed. The DIPG subgroup was statistically associated with HIF2 hyperexpression and the complete absence of mTor expression. At the transcriptomic level, most of the tumors were overexpressing constantly and mainly RAS, HIF1, RPS6KB1, VHL, ENG and VEGFA, whereas mTOR, AKT, CXCL12 and CXCR4 were modulated throughout the tumors’ cohort. The metabolomic profiles showed a constant activated glycolysis in all tumors, whereas glutaminolysis and seronolysis were heterogeneously present. The only significant association was the presence of the lipolytic pathways and HIF2 hyperexpression, as already linked in our previous work. The combination of new drugs targeting hypoxia biomarkers and metabolic pathways like glycolysis and/or lipolysis might be a new approach in pHGG and DIPG.
Bendamustine plus rituximab for chronic cold agglutinin disease: results of a Nordic prospective multicenter trial
Authors: Sigbjørn Berentsen, Ulla Randen, Markku Oksman, Henrik Birgens, Tor Henrik Anderson Tvedt, Jakob Dalgaard, Eivind Galteland, Einar Haukås, Robert Brudevold, Jon Hjalmar Sørbø, Inger Anne Næss, Agnieszka Malecka, Geir E. Tjønnfjord
Journal: Blood (2017)
Sixty Years of Placebo-Controlled Antipsychotic Drug Trials in Acute Schizophrenia: Systematic Review, Bayesian Meta-Analysis, and Meta-Regression of Efficacy Predictors
Authors: Stefan Leucht, Claudia Leucht, Maximilian Huhn, Anna Chaimani, Dimitris Mavridis, Bartosz Helfer, Myrto Samara, Matteo Rabaioli, Susanne Bächer, Andrea Cipriani, John R. Geddes, Georgia Salanti, John M. Davis
Journal: American Journal of Psychiatry (2017)

Antipsychotic drug efficacy may have decreased over recent decades. The authors present a meta-analysis of all placebo-controlled trials in patients with acute exacerbations of schizophrenia, and they investigate which trial characteristics have changed over the years and which are moderators of drug-placebo efficacy differences.The search included multiple electronic databases. The outcomes were overall efficacy (primary outcome); responder and dropout rates; positive, negative, and depressive symptoms; quality of life; functioning; and major side effects. Potential moderators of efficacy were analyzed by meta-regression.The analysis included 167 double-blind randomized controlled trials with 28,102 mainly chronic participants. The standardized mean difference (SMD) for overall efficacy was 0.47 (95% credible interval 0.42, 0.51), but accounting for small-trial effects and publication bias reduced the SMD to 0.38. At least a "minimal" response occurred in 51% of the antipsychotic group versus 30% in the placebo group, and 23% versus 14% had a "good" response. Positive symptoms (SMD 0.45) improved more than negative symptoms (SMD 0.35) and depression (SMD 0.27). Quality of life (SMD 0.35) and functioning (SMD 0.34) improved even in the short term. Antipsychotics differed substantially in side effects. Of the response predictors analyzed, 16 trial characteristics changed over the decades. However, in a multivariable meta-regression, only industry sponsorship and increasing placebo response were significant moderators of effect sizes. Drug response remained stable over time.Approximately twice as many patients improved with antipsychotics as with placebo, but only a minority experienced a good response. Effect sizes were reduced by industry sponsorship and increasing placebo response, not decreasing drug response. Drug development may benefit from smaller samples but better-selected patients.
TRTH-04. POTENTIAL OF NANO-FIBER PEPTIDE (NFP)-CONJUGATED THERAPEUTICS FOR LOCAL CONVECTION-ENHANCED DELIVERY (CED) IN CNS TUMORS
Authors: Umberto Tosi, Vanessa Bellat, Hari Krishna Kommidi, Melanie Schweitzer, Sarah Guo, Christopher Marnell, Uday Bhanu Maachani, Richard Ting, Benedict Law, Mark Souweidane
Journal: Neuro-Oncology (2017)

The tightly regulated blood-brain barrier (BBB) poses a challenge to systemic drug administration aimed at reaching the brain parenchyma. As such, recent efforts have focused on convection-enhanced delivery (CED), a technique that relies on direct catheter implantation into the target tissue to allow for high regional concentration of infusate. One of the major challenges of CED is the rapid clearance of small molecules, an issue that warrants the use of multiple injections or of implanted devices. CED has been shown to provide a suitable means of delivery for large drug carriers like nanoparticles and nanofibers. In this study, we evaluate the therapeutic potential of self-assembling, non-immunogenic, non-toxic, 400 nm-long, nano-fiber peptides (NFPs). These constructs were created to be coupled with therapeutics of choice, which are ‘unloaded’ at the desired site. In this study, we evaluate the feasibility of this technology in vivo. NFPs were coupled with 89Zr and injected via CED into the frontal lobe [MMS1]of naïve mice. Their kinetics were monitored via PET/CT for up to three weeks following injection. We find that NFPs have an estimated clearance half-life from site of injection of 80 days (significantly greater than the decay half-life of 89Zr, approximately 3 days), thus making NFPs a suitable vector for the retaining therapeutic concentrations of small molecules into the brain, and significantly increasing bioavailability (currently, small molecules clear from the brain parenchyma in a few hours). NFP clearance eventually occurs via the hepatosplenic route and no significant neurotoxicity is observed. Future efforts will focus on drug conjugation to non-radioactive NFPs.
Fixations are not all created equal: An objection to mindless visual search
Authors: James T Enns, Marcus R Watson
Journal: Behavioral and Brain Sciences (2017)

Abstract This call to revolution in theories of visual search does not go far enough. Treating fixations as uniform is an oversimplification that obscures the critical role of the mind. We remind readers that what happens during a fixation depends on mindset, as shown in studies of search strategy and of humans' ability to rapidly resume search following an interruption.
Abstract 348: p38γ and δ Promote Heart Hypertrophy by Targeting the Mtor-inhibitory Protein Deptor for Degradation
Authors: Bárbara González-Terán, Juan A López, Elena Rodríguez, Luis Leiva, Sara Martínez-Martínez, Luis J Jiménez-Borreguero, Juan M Redondo, Jesús Vazquez, Guadalupe Sabio
Journal: Circulation Research (2015)

Disrupted organ growth underlies the development of several diseases. Whereas the fetal heart grows mainly through proliferation, the postnatal heart grows through hypertrophy. Hypertrophy is also activated in the adult heart as a compensatory response to stress, but chronic ventricular hypertrophy leads to heart failure. The molecular mechanisms underlying ventricular hypertrophy are unknown. We show that cardiac expression and activation of p38γ and p38δ increases during postnatal development and these kinases are activated by the hypertrophy-inducing stress stimuli angiotensin II and phenylephrine. p38γ and p38δ promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, promoting its degradation and thereby activating mTORC1 and mTORC2. Hearts from mice lacking one or both kinases were below-normal size, had high levels of DEPTOR and consequently low activity of the mTOR pathway, and reduced protein synthesis. The mTOR inhibitor, rapamycin, equalized heart weight in wild-type and p38γ/δ-/- mice. Moreover, p38γ/δ-/- mice were protected against pathological ventricular hypertrophy, establishing p38γ/δ as key regulators of this process.
Re: Maria Carmen Mir, Ithaar Derweesh, Francesco Porpiglia, Homayoun Zargar, Alexandre Mottrie, Riccardo Autorino. Partial Nephrectomy Versus Radical Nephrectomy for Clinical T1b and T2 Renal Tumors: A Systematic Review and Meta-analysis of Comparative Studies. Eur Urol 2017;71:606–17
Authors: Jae Heon Kim, Benjamin I. Chung
Journal: European Urology (2017)
A metabolomics-based biomarker signature discriminates pancreatic cancer from chronic pancreatitis
Authors: Eithne Costello
Journal: Gut (2017)

The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing. The projection that it will surpass breast cancer to become the second-leading cause of cancer-related deaths by 2030 serves as a wake-up call to stakeholders, including healthcare systems and researchers.1 Earlier diagnosis is one factor that could alter this trajectory. Correspondingly, the research community has made substantial efforts to find biomarkers that will enable the diagnosis of pancreatic cancer at a stage where it can be successfully treated.2 There are however, significant challenges. Pancreatic cancer is a very heterogeneous disease with great interindividual variation, as well as significant heterogeneity within the tumours of individuals.3 4 This calls for large sample sizes to ensure adequate representation of subtypes. Moreover, biomarker development programmes require samples to be separated into independent training and test sets, further increasing the quantity of samples needed. However, the number of new cases of pancreatic cancer per year is low compared with other common cancers. Therefore, in order to acquire sufficient samples of patients with cancer and control individuals for biomarker studies, multicentre collaborations are essential. Such collaborations require orchestration, as the use of standardised protocols for collection and storage of both case and control samples across centres …
Arterial resistance
Authors: Hussein Mousa Atta, Michael J. Henderson, Ricardo Mastai, Jaime Bosch
Journal: Hepatology (1990)

We read with interest the paper by Mastai and coworkers (1) in the September 1989 issue of HEPA-TOLOGY.This paper showed that in patients with cirrhosis and end-to-side portacaval shunts, intravenous infusion of propranolol leads to decreases in cardiac output and hepatic artery blood flow and increases in systemic and hepatic arterial vascular resistances.However, we believe the authors have made a fundamental error in the presentation of their data on hepatic arterial resistance.Total systemic vascular resistance (Rs) is the sum of many resistances (Rl, R,, R,, . ..)
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease
Authors: Hao Lu, Maria C Rondón Galeano, Elisabeth Ott, Geraldine Kaeslin, P Jaya Kausalya, Carina Kramer, Nadina Ortiz-Brüchle, Nadescha Hilger, Vicki Metzis, Milan Hiersche, Shang Yew Tay, Robert Tunningley, Shubha Vij, Andrew D Courtney, Belinda Whittle, Elke Wühl, Udo Vester, Björn Hartleben, Steffen Neuber, Valeska Frank, Melissa H Little, Daniel Epting, Peter Papathanasiou, Andrew C Perkins, Graham D Wright, Walter Hunziker, Heon Yung Gee, Edgar A Otto, Klaus Zerres, Friedhelm Hildebrandt, Sudipto Roy, Carol Wicking, Carsten Bergmann
Journal: Nature Genetics (2017)