tbuckley/cabot-search huggingface dataset:
Complement C3-Targeted Gene Therapy Restricts Onset and Progression of Neurodegeneration in Chronic Mouse Glaucoma
Authors: Alejandra Bosco, Sarah R. Anderson, Kevin T. Breen, Cesar O. Romero, Michael R. Steele, Vince A. Chiodo, Sanford L. Boye, William W. Hauswirth, Stephen Tomlinson, Monica L. Vetter
Journal: Molecular Therapy (2018)

Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve and retinal damage in glaucoma is preceded by local complement upregulation and activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because complement signals through three pathways that intersect at complement C3 activation, here we targeted this step to restore complement balance in the glaucomatous retina and to determine its contribution to degeneration onset and/or progression. To achieve this, we combined adeno-associated virus retinal gene therapy with the targeted C3 inhibitor CR2-Crry. We show that intravitreal injection of AAV2.CR2-Crry produced sustained Crry overexpression in the retina and reduced deposition of the activation product complement C3d on retinal ganglion cells and the inner retina of DBA/2J mice. This resulted in neuroprotection of retinal ganglion cell axons and somata despite continued intraocular pressure elevation, suggesting a direct restriction of neurodegeneration onset and progression and significant delay to terminal disease stages. Our study uncovers a damaging effect of complement C3 or downstream complement activation in glaucoma, and it establishes AAV2.CR2-Crry as a viable therapeutic strategy to target pathogenic C3-mediated complement activation in the glaucomatous retina. Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve and retinal damage in glaucoma is preceded by local complement upregulation and activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because complement signals through three pathways that intersect at complement C3 activation, here we targeted this step to restore complement balance in the glaucomatous retina and to determine its contribution to degeneration onset and/or progression. To achieve this, we combined adeno-associated virus retinal gene therapy with the targeted C3 inhibitor CR2-Crry. We show that intravitreal injection of AAV2.CR2-Crry produced sustained Crry overexpression in the retina and reduced deposition of the activation product complement C3d on retinal ganglion cells and the inner retina of DBA/2J mice. This resulted in neuroprotection of retinal ganglion cell axons and somata despite continued intraocular pressure elevation, suggesting a direct restriction of neurodegeneration onset and progression and significant delay to terminal disease stages. Our study uncovers a damaging effect of complement C3 or downstream complement activation in glaucoma, and it establishes AAV2.CR2-Crry as a viable therapeutic strategy to target pathogenic C3-mediated complement activation in the glaucomatous retina.
Abstract 18111: The Adipokine Resistin-Like Molecule Alpha Potentiates Angiogenesis in Heart Failure Mice Model the Adipokine Resistin-Like Molecule Alpha Potentiates Angiogenesis in Heart Failure Mice Model
Authors: Wan Seok Kang, Soo Yeon Lim, Yong Sook Kim, Youngkeun Ahn
Journal: Circulation (2016)

Introduction: Resistin-like molecule alpha (Retnla) is a marker for anti-inflammatory macrophages. The vital roles of retnla were studied in atherosclerosis, however, the role in heart failure rema...
Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab
Authors: Mariaelena Capone, Diana Giannarelli, Domenico Mallardo, Gabriele Madonna, Lucia Festino, Antonio Maria Grimaldi, Vito Vanella, Ester Simeone, Miriam Paone, Giuseppe Palmieri, Ernesta Cavalcanti, Corrado Caracò, Paolo Antonio Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2018)

Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors.This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves.In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60-5.08; p < 0.0001) and LDH (HR = 2.51; 95% CI 1.36-4.64; p < 0.0001) maintained a significant association with OS in multivariate analysis. Patients with baseline NLR ≥5 had significantly worse OS and PFS than patients with NLR < 5, as did patients with baseline dNLR ≥3 versus < 3. Optimal cut-off values were ≥ 4.7 for NLR and ≥ 3.8 for dNLR. Using this ≥4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR< 3.8 was also associated with better OS and PFS.Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma.
China vaccine scandal: investigations begin into faulty rabies and DTaP shots
Authors: Flynn Murphy
Journal: BMJ (2018)

Trust in China’s authorities to guarantee the safety of medicines has been shaken after the nation’s second largest producer of rabies vaccines was found to have faked records.

Changsheng Biotechnology, based in the northeastern Jilin province, was ordered to cease producing a Vero cell based rabies vaccine on 15 July after China’s State Food and Drug Administration found that it had forged production and inspection data, the regulator said.1 Investigators reportedly acted on a tip-off from an ex-employee.

Changsheng issued an apology and announced a recall as shares in the company tumbled. It was not clear whether the batches had been released to market or how the substandard vaccine might affect people, but …
Corrigendum to ‘The number of positive lymph node is a better predictor of survival than the lymph node metastasis status for pancreatic neuroendocrine neoplasms: A retrospective cohort study’ [Int. J. Surg. 48 (2017) 142–148]
Authors: Xianbin Zhang, Lili Lu, Yuru Shang, Peng Liu, Yushan Wei, Li Ma, Peng Gong
Journal: International Journal of Surgery (2018)
The health and economic outcomes of early egg introduction strategies
Authors: Marcus Shaker, Kanak Verma, Matthew Greenhawt
Journal: Allergy (2018)

Abstract Background Studies suggest early egg introduction ( EEI ) in the first year of life is associated with reduced risk of developing egg allergy. No US recommendations exist regarding optimally implementing EEI . Methods Using simulation and Markov modelling over a 20‐year horizon, we explored optimal EEI strategies applied to US , European and Canadian populations, comparing screening of high‐risk infants (skin prick testing [SPT] or serum‐specific IgE[ sIgE ]) before introducing cooked egg at 6 months of life vs egg introduction at home, without screening, for all infants. Results A no‐screen approach dominated egg SPT screening of high‐risk infants with early‐onset eczema. Base model per‐patient incremental costs of SPT were $6865 US dollars ( USD ), 6801 euros and $10 610 Canadian dollars ( CAD ). For egg sIgE screening in primary care settings, base model incremental costs were $16 722 USD , 18 072 euros and $28 193 CAD . As the simulation concluded 2.5% were egg allergic without screening vs 9.5%, 12% and 21.4% of children undergoing SPT , delayed introduction or sIgE screening. Incremental societal costs from screening reached $2 009 351 175 USD for SPT and $4 894 445 790 USD for sIgE testing. In sensitivity analyses, if the risk of reaction with initial egg ingestion was ≥22.5%, SPT before EEI became a preferred strategy. A no‐screen approach dominated both EEI of raw pasteurized egg and delayed cooked egg introduction approaches. Conclusions Assuming initial reaction rates &lt; 22.5%, a no‐screening EEI cooked egg approach has superior health and economic benefits in terms of number of egg allergy cases prevented and total healthcare costs vs screening testing.
Abstract 18883: High Sensitivity Troponin T in Acute Heart Failure: Insights from RELAX-AHF
Authors: G. Michael Felker, Robert J Mentz, J R Teerlink, A A Voors, P S Pang, P Ponikowski, B H Greenberg, G Filippatos, B A Davison, G Cotter, M F Prescott, T Hua, T Severin, M Metra
Journal: Circulation (2014)

Background: Elevations of cardiac troponin are common in acute heart failure (AHF), but their clinical importance is uncertain. We examined the association between serial high-sensitivity troponin T (hs-cTnT) and outcomes in the RELAX-AHF study, a randomized trial of IV serelaxin in AHF. Methods: hs-cTnT (Roche Diagnostics) was measured at baseline and days 2, 5, and 14. Patients with clinical evidence of ACS were excluded by protocol. 1074 patients (93% of total cohort) with data available for both baseline and at least 1 follow-up hs-cTnT measurement were analyzed. We assessed the relationship between baseline hs-cTnT and peak change from baseline hs-cTnT with outcomes. Models were adjusted for other clinical variables and treatment assignment. Differential effect of serelaxin by troponin levels was assessed by interactions terms. Results: The median baseline troponin was 0.033 mcg/L, and 95% were above the 99 th upper reference limit (URL). Patients with elevated hs-cTnT were more likely to be men with ischemic heart disease, worse renal function, and higher natriuretic peptides. Both higher baseline hs-cTnT and greater peak hs-cTnT were associated with increased risk for adverse outcomes even after adjustment ( Table ). Treatment effect of serelaxin did not differ based on troponin status. Conclusion: Consistent with prior data, hs-cTnT was elevated above the 99% URL in the vast majority of AHF patients at baseline, and was associated with markers of disease severity. Both baseline and peak change from baseline hs-cTnT were associated with worse clinical outcomes, but relationships were generally strongest for 180-day CV mortality. Treatment effect of serelaxin did not differ based on troponin status.
Review: In adults with type 1 diabetes, SGLT-2 inhibitors reduce HbA<sub>1c</sub>but increase diabetic ketoacidosis
Authors: Aoife M. Egan, Victor M. Montori
Journal: Annals of Internal Medicine (2018)

Source Citation Yamada T, Shojima N, Noma H, Yamauchi T, Kadowaki T. Sodium–glucose co-transporter-2 inhibitors as add-on therapy to insulin for type 1 diabetes mellitus: Systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2018;20:1755-61. 29451721
Review: After PCI in AF, OAC plus single vs dual antiplatelets reduces major bleeding; no difference for MACE
Authors: Dennis G. Maki
Journal: Annals of Internal Medicine (2018)

ACP Journal Club17 July 2018Review: After PCI in AF, OAC plus single vs dual antiplatelets reduces major bleeding; no difference for MACEDennis G. Maki, MD, MACPDennis G. Maki, MD, MACPUniversity of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA (D.G.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2018-169-2-008 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationKhan SU, Khan MU, Ghani AR, et al. Meta-analysis of antithrombotic therapy in atrial fibrillation after percutaneous coronary intervention. Am J Cardiol. 2018;121:1200-6. https://pubmed.ncbi.nlm.nih.gov/29548674Clinical Impact RatingsGIM/FP/GP: Cardiology: References1 January CT, Wann LS, Alpert JS, et al; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130:2071-104. [PMID: 24682348] Google Scholar2 Chen CF, Chen B, Zhu J, Xu YZ. Antithrombotic therapy after percutaneous coronary intervention in patients requiring oral anticoagulant treatment. A meta-analysis. Herz. 2015;40:1070-83. [PMID: 26135462] Google Scholar3 Chen J, Wang LY, Deng C, Jiang XH, Chen TG. The safety and efficacy of oral anticoagulants with dual versus single antiplatelet therapy in patients after percutaneous coronary intervention: a meta-analysis. Medicine (Baltimore). 2017;96:e8015. [PMID: 28906384] Google Scholar4 Agarwal N, Jain A, Mahmoud AN, et al. Safety and efficacy of dual versus triple antithrombotic therapy in patients undergoing percutaneous coronary intervention. Am J Med. 2017;130:1280-9. [PMID: 28460853] Google Scholar5 Cavallari I, Patti G. Meta-analysis comparing the safety and efficacy of dual versus triple antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention. Am J Cardiol. 2018;121:718-24. [PMID: 29373105] Google Scholar Author, Article, and Disclosure InformationAffiliations: University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA (D.G.M.)This article was published at Annals.org on 3 July 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 17 July 2018Volume 169, Issue 2Page: JC8KeywordsAntiplatelet therapyAtrial fibrillationHemorrhageMyocardial infarctionNumber needed to treatObservational studiesPercutaneous coronary interventionSafetyStent implantationStroke ePublished: 17 July 2018 Issue Published: 17 July 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Training and validation of a novel 4-miRNA ratio model (MiCaP) for prediction of postoperative outcome in prostate cancer patients
Authors: L. Schmidt, J. Fredsøe, H. Kristensen, S.H. Strand, A. Rasmussen, S. Høyer, M. Borre, P. Mouritzen, T. Ørntoft, K.D. Sørensen
Journal: Annals of Oncology (2018)

New molecular biomarkers for prostate cancer (PC) prognosis are urgently needed. Ratio-based models are attractive, as they require no additional normalization. Here, we train and independently validate a novel 4-miRNA prognostic ratio model for PC.By genome-wide miRNA expression profiling of PC tissue samples from 123 men who underwent radical prostatectomy (RP) (PCA123, training cohort), we identified six top candidate prognostic miRNAs and systematically tested their ability to predict postoperative biochemical recurrence (BCR). The best miRNA-based prognostic ratio model (MiCaP) was validated in two independent cohorts (PCA352 and PCA476) including >800 RP patients in total. Clinical end points were BCR and prostate cancer-specific survival (CSS). The prognostic potential of MiCaP was assessed by univariate and multivariate Cox-regression analyses and Kaplan-Meier analyses.We identified a 4-miRNA ratio model, MiCaP (miR-23a-3p×miR-10b-5p)/(miR-133a×miR-374b-5p), that predicted time to BCR independently of routine clinicopathologic variables in the training cohort (PCA123) and was successfully validated in two independent RP cohorts. In addition, MiCaP was a significant predictor of CSS in univariate analysis [HR 3.35 (95% CI 1.34 - 8.35), P = 0.0096] and in multivariate analysis [HR 2.43 (95% CI 1.45-4.07), P = 0.0210]. As proof-of-principle, we also analyzed MiCaP in plasma samples from 111 RP patients. A high MiCaP score in plasma was significantly associated with BCR (P = 0.0036, Kaplan-Meier analysis). Limitations include low mortality rates (CSS: 5.4%).We identified a novel 4-miRNA ratio model (MiCaP) with significant independent prognostic value in three RP cohorts, indicating promising potential to improve PC risk stratification.
An approach to identify a minimum and rational proportion of caesarean sections in resource-poor settings: a global network study
Authors: José M Belizán, Nicole Minckas, Elizabeth M McClure, Sarah Saleem, Janet L Moore, Shivaprasad S Goudar, Fabian Esamai, Archana Patel, Elwyn Chomba, Ana L Garces, Fernando Althabe, Margo S Harrison, Nancy F Krebs, Richard J Derman, Waldemar A Carlo, Edward A Liechty, Patricia L Hibberd, Pierre M Buekens, Robert L Goldenberg
Journal: The Lancet Global Health (2018)

Caesarean section prevalence is increasing in Asia and Latin America while remaining low in most African regions. Caesarean section delivery is effective for saving maternal and infant lives when they are provided for medically-indicated reasons. On the basis of ecological studies, caesarean delivery prevalence between 9% and 19% has been associated with better maternal and perinatal outcomes, such as reduced maternal land fetal mortality. However, the specific prevalence of obstetric and medical complications that require caesarean section have not been established, especially in low-income and middle-income countries (LMICs). We sought to provide information to inform the approach to the provision of caesarean section in low-resource settings.We did a literature review to establish the prevalence of obstetric and medical conditions for six potentially life-saving indications for which caesarean section could reduce mortality in LMICs. We then analysed a large, prospective population-based dataset from six LMICs (Argentina, Guatemala, Kenya, India, Pakistan, and Zambia) to determine the prevalence of caesarean section by indication for each site. We considered that an acceptable number of events would be between the 25th and 75th percentile of those found in the literature.Between Jan 1, 2010, and Dec 31, 2013, we enrolled a total of 271 855 deliveries in six LMICs (seven research sites). Caesarean section prevalence ranged from 35% (3467 of 9813 deliveries in Argentina) to 1% (303 of 16 764 deliveries in Zambia). Argentina's and Guatemala's sites all met the minimum 25th percentile for five of six indications, whereas sites in Zambia and Kenya did not reach the minimum prevalence for caesarean section for any of the indications. Across all sites, a minimum overall caesarean section of 9% was needed to meet the prevalence of the six indications in the population studied.In the site with high caesarean section prevalence, more than half of the procedures were not done for life-saving conditions, whereas the sites with low proportions of caesarean section (below 9%) had an insufficient number of caesarean procedures to cover those life-threatening causes. Attempts to establish a minimum caesarean prevalence should go together with focusing on the life-threatening causes for the mother and child. Simple methods should be developed to allow timely detection of life-threatening conditions, to explore actions that can remedy those conditions, and the timely transfer of women with those conditions to health centres that could provide adequate care for those conditions.Eunice Kennedy Shriver National Institute of Child Health and Human Development.
The Innate Immune Receptors TLR2/4 Mediate Repeated Social Defeat Stress-Induced Social Avoidance through Prefrontal Microglial Activation
Authors: Xiang Nie, Shiho Kitaoka, Kohei Tanaka, Eri Segi-Nishida, Yuki Imoto, Atsubumi Ogawa, Fumitake Nakano, Ayaka Tomohiro, Kazuki Nakayama, Masayuki Taniguchi, Yuko Mimori-Kiyosue, Akira Kakizuka, Shuh Narumiya, Tomoyuki Furuyashiki
Journal: Neuron (2018)
Effectiveness of a hospital-wide infection control programme on the incidence of healthcare-associated infections and associated severe sepsis and septic shock: a prospective interventional study
Authors: S. Hagel, K. Ludewig, M.W. Pletz, J. Frosinski, A. Moeser, M. Wolkewitz, P. Gastmeier, S. Harbarth, F.M. Brunkhorst, M. Kesselmeier, A. Scherag
Journal: Clinical Microbiology and Infection (2018)

ObjectivesTo evaluate whether a hospital-wide infection control programme (ICP) is effective at reducing the burden of healthcare-associated infections (HAIs) and associated severe sepsis/septic shock or death (severe HAIs).MethodsProspective, quasi-experimental study with two surveillance periods (September 2011 to August 2012; May 2013 to August 2014). Starting October 2012, the ICP included hand hygiene promotion and bundle implementation for common HAIs. We applied segmented mixed-effects Poisson regression and multi-state models. We reported adjusted incidence rate ratios (aIRR) and adjusted hazard ratios (aHR) with 95% confidence intervals (CI).ResultsOverall, 62 154 patients were under surveillance, with 1568 HAIs identified in 1170 patients (4.3 per 100 admissions) in the first and 2336 HAIs identified in 1711 patients (4.9 per 100 admissions) in the second surveillance period. No differences were found in the overall HAI incidence rates between the periods in the general wards (aIRR 1.29, 95% CI 0.78–2.15) and intensive care units (ICUs) (aIRR 0.59, 95% CI 0.27–1.31). However, the HAI incidence rate was declining in the ICUs after starting the ICP (aIRR 0.98, 95% CI 0.97–1.00 per 1-week increment), in contrast to general wards (aIRR 1.01, 95% CI 1.00–1.02). A reduction in severe HAIs (aIRR 0.13, 95% CI 0.05–0.32) and a lower probability of HAI-associated in-hospital deaths (aHR 0.56, 95% CI 0.31–0.99) were observed in the second period in the ICUs.ConclusionsThere was no overall reduction in HAIs after implementation of the ICP. However, there was a significant reduction in severe HAIs in ICUs. Whether this difference was a consequence of the ICP or improvement in HAI case management is not clear.
Ancestral Adeno-Associated Virus Vector Delivery of Opsins to Spiral Ganglion Neurons: Implications for Optogenetic Cochlear Implants
Authors: Maria J. Duarte, Vivek V. Kanumuri, Lukas D. Landegger, Osama Tarabichi, Sumi Sinha, Xiankai Meng, Ariel Edward Hight, Elliott D. Kozin, Konstantina M. Stankovic, M. Christian Brown, Daniel J. Lee
Journal: Molecular Therapy (2018)

Optogenetics is a transformative technology based on light-sensitive microbial proteins, known as opsins, that enable precise modulation of neuronal activity with pulsed radiant energy. Optogenetics has been proposed as a means to improve auditory implant outcomes by reducing channel interaction and increasing electrode density, but the introduction of opsins into cochlear spiral ganglion neurons (SGNs) in vivo has been challenging. Here we test opsin delivery using a synthetically developed ancestral adeno-associated virus (AAV) vector called Anc80L65. Wild-type C57BL/6 mouse pups were injected via the round window of cochlea with Anc80L65 carrying opsin Chronos under the control of a CAG promoter. Following an incubation of 6–22 weeks, pulsed blue light was delivered to cochlear SGNs via a cochleosotomy approach and flexible optical fiber. Optically evoked auditory brainstem responses (oABRs) and multiunit activity in inferior colliculus (IC) were observed. Post-experiment cochlear histology demonstrated opsin expression in SGNs (mean = 74%), with an even distribution of opsin along the cochlear basal/apical gradient. This study is the first to describe robust SGN transduction, opsin expression, and optically evoked auditory electrophysiology in neonatal mice. Ultimately, this work may provide the basis for a new generation of cochlear implant based on light.