tbuckley/cabot-search huggingface dataset:
Cost-effectiveness of the controlled temperature chain for the hepatitis B virus birth dose vaccine in various global settings: a modelling study
Authors: Nick Scott, Anna Palmer, Christopher Morgan, Olufunmilayo Lesi, C Wendy Spearman, Mark Sonderup, Margaret Hellard
Journal: The Lancet Global Health (2018)

The controlled temperature chain (CTC) strategy allows vaccines to be kept outside the cold chain for a short period of time. In remote rural areas, the CTC strategy for the hepatitis B virus (HBV) birth dose vaccination could improve its geographical coverage and timeliness of delivery, but with additional outreach costs. We assessed the cost-effectiveness of the CTC strategy for the HBV birth dose across six world regions and 72 countries according to their HBV prevalence, delivery costs, and birth dose coverage and timing.By use of a mathematical model of perinatal HBV transmission and disease progression, we calculated per 1000 births the total HBV-related disability-adjusted life-years (DALYs) and costs, including vaccine delivery costs and costs associated with HBV-related disease, with and without the CTC strategy.A CTC strategy produced health benefits in all regions and was cost-saving in the regions of east Asia and Pacific, Latin America and Caribbean, sub-Saharan Africa, and north Africa and Middle East. The CTC strategy cost US$0·15 (IQR -7·11 to 4·75) per DALY averted in the central and eastern Europe and central Asia region and $79·72 (66·47 to 94·47) in the south Asia region. Within individual countries, more savings were achieved and more DALYs averted in areas with above average HBV prevalence, below average birth dose coverage, or later than average birth dose delivery.A CTC outreach strategy that improves the timing and coverage of the HBV birth dose vaccination is likely to be cost-saving and reduce the burden of HBV infection associated with perinatal transmission.Burnet Institute.
IFN-γ Enhances the Cough Reflex Sensitivity via Calcium Influx in Vagal Sensory Neurons
Authors: Zheng Deng, Wenliang Zhou, Jiayang Sun, Chenhui Li, Bonian Zhong, Kefang Lai
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Cough hypersensitivity syndrome is often triggered by a viral infection. The viral infection might trigger cough hypersensitivity via increasing the release of IFN-γ from T lymphocytes in the lung.To investigate effects of IFN-γ on the vagal sensory neurons and the cough reflex.Effects of IFN-γ on the cough reflex were investigated in guinea pigs. Cellular immunofluorescence imaging, calcium imaging, and patch clamp techniques were used to study effects of IFN-γ in primary cultured rat vagal sensory neurons.Intratracheal instillation of IFN-γ enhanced the cough response to citric acid in vivo. IFN-γ significantly increased levels of phosphorylated signal transducer and activator of transcription-1 but not phosphorylated transient receptor potential vanilloid 1 in vitro. Not only did IFN-γ enhance the response of neurons to capsaicin and electric stimulation, but also it directly induced Ca2+ influx, membrane depolarization, and action potentials in neurons via the Janus kinase, protein kinase A, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid pathways. However, IFN-γ did not elicit Ca2+ release from the endoplasmic reticulum via the phospholipase C pathway. Although IFN-γ-induced action potentials were suppressed by Ca2+ influx inhibitors, IFN-γ-induced Ca2+ influx was not altered by an inhibitor of rapid sodium channels.The membrane potential in vagal sensory neurons may be depolarized by IFN-γ-induced Ca2+ influx. The depolarization of membrane potentials may enhance the cough reflex sensitivity and cause action potentials. IFN-γ may be a new target for treating cough hypersensitivity syndrome and postviral cough.
Eosinophilic oesophagitis endotype classification by molecular, clinical, and histopathological analyses: a cross-sectional study
Authors: Tetsuo Shoda, Ting Wen, Seema S Aceves, J Pablo Abonia, Dan Atkins, Peter A Bonis, Julie M Caldwell, Kelley E Capocelli, Christina L Carpenter, Margaret H Collins, Evan S Dellon, Michael D Eby, Nirmala Gonsalves, Sandeep K Gupta, Gary W Falk, Ikuo Hirano, Paul Menard-Katcher, Jonathan T Kuhl, Jeffrey P Krischer, John Leung, Vincent A Mukkada, Jonathan M Spergel, Michael P Trimarchi, Guang-Yu Yang, Nives Zimmermann, Glenn T Furuta, Marc E Rothenberg
Journal: The Lancet. Gastroenterology & hepatology (2018)
Site-specific stabilization of minigastrin analogs against enzymatic degradation for enhanced cholecystokinin-2 receptor targeting
Authors: Maximilian Klingler, Clemens Decristoforo, Christine Rangger, Dominik Summer, Julie Foster, Jane K Sosabowski, Elisabeth von Guggenberg
Journal: Theranostics (2018)

Minigastrin (MG) analogs show high affinity to the cholecystokinin-2 receptor (CCK2R) and have therefore been intensively studied to find a suitable analog for imaging and treatment of CCK2R-expressing tumors. The clinical translation of the radioligands developed thus far has been hampered by high kidney uptake or low enzymatic stability. In this study, we aimed to develop new MG analogs with improved targeting properties stabilized against degradation through site-specific amino acid modifications. Method: Based on the lead structure of a truncated MG analog, four new MG derivatives with substitutions in the C-terminal part of the peptide (Trp-Met-Asp-Phe-NH2) were synthesized and derivatized with DOTA at the N-terminus for radiolabeling with trivalent radiometals. The in vitro properties of the new analogs were characterized by analyzing the lipophilicity, the protein binding, and the stability of the Indium-111 (111In)-labeled analogs in different media. Two different cell lines, AR42J cells physiologically expressing the rat CCK2R and A431 cells transfected with human CCK2R (A431-CCK2R), were used to study the receptor affinity and cell uptake. For the two most promising MG analogs, metabolic studies in normal BALB/c mice were carried out as well as biodistribution and imaging studies in tumor xenografted athymic BALB/c nude mice. Results: Two out of four synthesized peptide analogs (DOTA-MGS1 and DOTA-MGS4) showed retained receptor affinity and cell uptake when radiolabeled with 111In. These two peptide analogs, however, showed a different stability against enzymatic degradation in vitro and in vivo. When injected to normal BALB/c mice, for 111In-DOTA-MGS1 at 10 min post injection (p.i.) no intact radiopeptide was found in the blood, whereas for 111In-DOTA-MGS4 more than 75% was still intact. 111In-DOTA-MGS4 showed a clear increase in injected activity per gram tissue (IA/g) for A431-CCK2R xenografts (10.40±2.21% IA/g 4 h p.i.) when compared to 111In-DOTA-MGS1 (1.23±0.15% IA/g 4 h p.i.). The tumor uptake of 111In-DOTA-MGS4 was also combined with a low uptake in stomach and kidney leading to high-contrast NanoSPECT/CT images. Conclusion: Of the four new MG analogs developed, the best results in terms of enzymatic stability and increased tumor targeting were obtained with 111In-DOTA-MGS4 showing two substitutions with N-methylated amino acids. 111In-DOTA-MGS4 was also superior to other MG analogs reported thus far and seems therefore an extremely promising targeting molecule for theranostic use with alternative radiometals.
Safety and efficacy of dose escalated liposomal amphotericin B in adult leukemia patients with refractory invasive fungal infections: A single institution report.
Authors: Sherry Mathew, Stephen Harnicar, Elizabeth Halton, Ellin Berman, Renier J. Brentjens, Mark L. Heaney, Joseph G. Jurcic, Nicole Lamanna, Peter George Maslak, Todd L. Rosenblat, Nelly G. Adel, Mark G. Frattini
Journal: Journal of Clinical Oncology (2012)

6613 Background: Leukemia patients are at risk for invasive fungal infections(IFI). Empiric therapy of suspected IFI is begun due to fever despite appropriate antibiotics during neutropenia or infiltrates on chest CT. Liposomal amphotericin B (L-AmB) is used for empiric anti-fungal therapy at 3-5 mg/kg. Data is lacking on the efficacy of L-AmB dose escalation in patients with CT progression and clinical decline. Methods: Patients who received 10 mg/kg of L-AmB from 2002-11. They were required to be ≥18 years old and escalated from 5 to 10 mg/kg L-Amb for at least 7 doses. Patient information was collected from pharmacy and medical records. Successful treatment was defined as resolution of fever at least 1 week after high dose L-AmB and/or improvement or stability on chest CT. Renal and hepatic toxicity was assessed. Clinical remission was defined as recovery of a normal neutrophil count. IRB approval was obtained for this study. Results: 58 patients were evaluated. At the time of presumed or probable IFI, 19 had completed induction therapy, 5 had received supportive therapy, and 34 had received 2 or more cycles of therapy. High dose L-AmB was begun for CT findings and fever, CT findings only, and fever only in 14, 26, and 17 patients, respectively. Patients received a median of 15 doses of high dose L-AmB, and all received concomitant therapy with an echinocandin except two: 1 received nothing and 1 received voriconazole. Treatment success was seen in 28 (48%) patients. Twenty-nine (50%) patients were alive at 12 weeks and 10 (17%) patients proceded to BMT. Only 11 (39%) of the responding patients achieved a clinical remission. All patients received IV hydration and electrolyte repletion. Six patients had a grade 2 increase in serum creatinine and 10 patients developed grade 2 or 3 hepatic toxicity. There were no grade 4 adverse events. Conclusions: Although it has been reported that L-AmB at 10mg/kg was inferior to 3 mg/kg in untreated patients, our study supports a safe dose escalation strategy to 10mg/kg in treating progressive presumed or probable IFI and should be considered a clinical alternative for these high risk patients.
US authorities recommend first approval of cannabis derived drug
Authors: Owen Dyer
Journal: BMJ (2018)

A US Food and Drug Administration expert advisory panel has voted by 13-0 to recommend approval of a cannabis based oral solution to treat two rare and severe forms of epilepsy.

Epidiolex, made by GW Pharma in the UK, is a cannabidiol product derived from Cannabis sativa plants that have been bred for low content of tetrahydrocannabinol, the psychoactive ingredient.

Three phase III clinical trials showed that the drug could reduce …
Lysosomes and Brain Health
Authors: Jaiprakash Sharma, Alberto di Ronza, Parisa Lotfi, Marco Sardiello
Journal: Annual Review of Neuroscience (2018)

One of the fundamental properties of the cell is the capability to digest and remodel its own components according to metabolic and developmental needs. This is accomplished via the autophagy-lysosome system, a pathway of critical importance in the brain, where it contributes to neuronal plasticity and must protect nonreplaceable neurons from the potentially harmful accumulation of cellular waste. The study of lysosomal biogenesis and function in the context of common and rare neurodegenerative diseases has revealed that a dysfunctional autophagy-lysosome system is the shared nexus where multiple, interconnected pathogenic events take place. The characterization of pathways and mechanisms regulating the lysosomal system and autophagic clearance offers unprecedented opportunities for the development of polyvalent therapeutic strategies based on the enhancement of the autophagy-lysosome pathway to maintain cellular homeostasis and achieve neuroprotection.
Development of a stress response therapy targeting aggressive prostate cancer
Authors: Hao G. Nguyen, Crystal S. Conn, Yae Kye, Lingru Xue, Craig M. Forester, Janet E. Cowan, Andrew C. Hsieh, John T. Cunningham, Charles Truillet, Feven Tameire, Michael J. Evans, Christopher P. Evans, Joy C. Yang, Byron Hann, Constantinos Koumenis, Peter Walter, Peter R. Carroll, Davide Ruggero
Journal: Science Translational Medicine (2018)

The PERK-eIF2α pathway is activated in aggressive prostate cancer and associated with patient outcome, providing a therapeutic target for the disease.
Sirtuins in Renal Health and Disease
Authors: Marina Morigi, Luca Perico, Ariela Benigni
Journal: Journal of the American Society of Nephrology (2018)

Sirtuins belong to an evolutionarily conserved family of NAD + -dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1–7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed.
New Insights from Studies of Clonal Hematopoiesis
Authors: Christopher J. Gibson, David P. Steensma
Journal: Clinical Cancer Research (2018)

Clonal hematopoiesis (CH) describes an asymptomatic expansion of blood cells descended from a single hematopoietic stem cell. Recent studies have shown that CH increases in frequency with aging and is often driven by somatic mutations in genes that are recurrently mutated in hematologic malignancies. When CH is associated with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or greater, it is termed "clonal hematopoiesis of indeterminate potential" (CHIP). CHIP has a 0.5% to 1% risk per year of progression to hematologic neoplasia, and increases both all-cause mortality and the risk of myocardial infarction and ischemic stroke due to a proinflammatory interaction between clonally derived leukocytes and vascular endothelium. CH frequently emerges in the context of immune-mediated marrow failure syndromes such as aplastic anemia, whereas CH emerging after cytotoxic cancer therapy is strongly associated with subsequent development of a therapy-related myeloid neoplasm, especially if a TP53 mutation is present. However, risk factors for developing CH other than aging, marrow failure, and cytotoxic radiotherapy or chemotherapy are poorly defined. In this review, we discuss the epidemiology, molecular mechanisms, and clinical consequences of this common and clinically important biological state. Clin Cancer Res; 24(19); 4633-42. ©2018 AACR.
Evolving prevalence and incidence trends of SCC of the anal canal: A SEER study.
Authors: Shunqing Zhang, Thomas A. DiPetrillo, Kara Lynne Leonard
Journal: Journal of Clinical Oncology (2018)

583 Background: The incidence of squamous cell carcinoma of the anal canal (SCCA) has been rising in the last three decades. With changing patient demographics and behaviors, the trends in prevalence and incidence of the disease have changed in recent years. Methods: The Surveillance, Epidemiology, and End Results (SEER) data set from 2000 to 2014 was analyzed for trends in prevalence and incidence of SCCA and for associated demographic and tumor characteristics including stage (localized vs. regional vs. distant disease), age (20-34, 35-49, 50-64, &gt; 65 years), and race/ethnicity (White, Black, American Indian/American Natives (AI/AN), American Pacific Islanders (API)). Results: 16,540 patients with SCCA were identified in the SEER database within the study period. The prevalence rate of SCCA was 0.01% (of 2000 standard U.S population), and the age-adjusted incidence rate of SCCA was 1.3/100,000. Prevalence and incidence was highest in patients age 50-64 and in the black population. Trend analysis of incidence demonstrated that while incidence rate continued to increase from 2000 to 2014, the average annual percentage change (APC) of incidence decreased from 4.80 before 2009 to 1.44 after. Patient population was divided into two groups: 2000-2008, with incidence of 1.6/100,000 and 2009-2014, with incidence of 2.1/100,000 (RR = 1.29, 95%CI = 1.25-1.33, p &lt; 0.001). Incidence in the 2009-2014 group increased compared to the 2000-2008 group among all staged SCCA, patients 50 years of age and older (RR = 1.41, p &lt; 0.001 and RR = 1.37, p &lt; 0.001 for age groups 50-64 and &gt; 65, respectively), and black (RR = 1.33, p &lt; 0.001) and white (RR = 1.32, p &lt; 0.001) race/ethnicity groups. APC in the 2009-2014 group decreased in all staged SCCA, increased in patients age 20-34, and decreased in all racial groups except AI/AN. Conclusions: There is a higher incidence and prevalence of SCCA in patients 50 years or older and in those of black ethnicity. Incidence of SCCA has increased in the US from 2000-2014, but the average APC in incidence has been decreasing except for in young patients and in those of AI/AN ethnicity. Awareness of disease prevalence and the pattern of change in incidence rate is important in the effort of disease prevention.
Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides
Authors: Benjamin Terrier, Christian Pagnoux, Élodie Perrodeau, Adexandre Karras, Chahera Khouatra, Olivier Aumaître, Pascal Cohen, Olivier Decaux, Hélène Desmurs-Clavel, François Maurier, Pierre Gobert, Thomas Quémeneur, Claire Blanchard-Delaunay, Bernard Bonnotte, Pierre-Louis Carron, Eric Daugas, Marize Ducret, Pascal Godmer, Mohamed Hamidou, Olivier Lidove, Nicolas Limal, Xavier Puéchal, Luc Mouthon, Philippe Ravaud, Loïc Guillevin
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Objective</h3> To compare long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides. <h3>Methods</h3> The 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial compared rituximab with azathioprine to maintain remission in patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis or renal-limited ANCA-associated vasculitis. Thereafter, prospective patient follow-up lasted until month 60. The primary endpoint was the major-relapse rate at month 60. Relapse and serious adverse event-free survival were also assessed. <h3>Results</h3> Among the 115 enrolled patients, only one was lost to follow-up at month 60. For the azathioprine and rituximab groups, respectively, at month 60, the major relapse-free survival rates were 49.4% (95% CI 38.0% to 64.3%) and 71.9% (95% CI 61.2% to 84.6%) (p=0.003); minor and major relapse-free survival rates were 37.2% (95% CI 26.5% to 52.2%) and 57.9% (95% CI 46.4% to 72.2%) (p=0.012); overall survival rates were 93.0% (95% CI 86.7% to 99.9%) and 100% (p=0.045) and cumulative glucocorticoid use was comparable. Quality-adjusted time without symptoms and toxicity analysis showed that rituximab-treated patients had 12.6 months more without relapse or toxicity than those given azathioprine (p&lt;0.001). Antiproteinase-3-ANCA positivity and azathioprine arm were independently associated with higher risk of relapse. HRs of positive ANCA to predict relapse increased over time. <h3>Conclusion</h3> The rate of sustained remission for ANCA-associated vasculitis patients, following rituximab-based or azathioprine-based maintenance regimens, remained superior over 60 months with rituximab, with better overall survival. <h3>Trial registration number</h3> NCT00748644.
Guideline: TMP–SMX is recommended after uncomplicated skin abscess incision and drainage
Authors: KoKo Aung
Journal: Annals of Internal Medicine (2018)

Source Citation Vermandere M, Aertgeerts B, Agoritsas T, et al. Antibiotics after incision and drainage for uncomplicated skin abscesses: a clinical practice guideline. BMJ. 2018 Feb 6;360:k243. 29437651
A dimeric form of a small-sized protein binder exhibits enhanced anti-tumor activity through prolonged blood circulation
Authors: Tae Yoon Kim, Hyo-Deok Seo, Joong-jae Lee, Jung Ae Kang, Woo Sik Kim, Hye-Min Kim, Ha-Yeon Song, Ji Min Park, Dong-Eun Lee, Hak-Sung Kim
Journal: Journal of Controlled Release (2018)
Death and Cardiac Arrest in U.S. Triathlon Participants
Authors: David Brown
Journal: Annals of Internal Medicine (2018)

Letters15 May 2018Death and Cardiac Arrest in U.S. Triathlon ParticipantsDavid Brown, MDDavid Brown, MDBaltimore, Maryland (D.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0022 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:I believe that Harris and colleagues (1) overlook the most obvious cause of deaths in triathlons: panic attacks followed by drowning or fatal arrhythmia. This was the conclusion I drew in an article I wrote in The Washington Post in 2011 that explored the unusual number of deaths—at least 9—that racing season (2). All but 1 of the deaths occurred in the swim segment.In my role as a science reporter for that publication, I attempted to contact relatives of all the victims. Survivors of 5 of the 8 swim-related victims were willing to talk. Four said ...References1. Harris KM, Creswell LL, Haas TS, Thomas T, Tung M, Isaacson E, et al. Death and cardiac arrest in U.S. triathlon participants, 1985 to 2016: a case series. Ann Intern Med. 2017;167:529-35. [PMID: 28975231]. doi:10.7326/M17-0847 LinkGoogle Scholar2. Brown D. Deaths in triathlons may not be so mysterious; panic attacks may be to blame. 14 November 2011. Accessed at www.washingtonpost.com/national/health-science/deaths-in-triathlons-may-not-be-so-mysterious-panic-attacks-may-be-to-blame/2011/10/24/gIQA70NrKN_story.html?utm_term=.bfd03229d6fd on 9 April 2018. Google Scholar3. The Washington Post. What's killing these triathlon competitors? The Washington Post live chat. 16 November 2011. Accessed at https://live.washingtonpost.com/deaths-in-triathlons-111116.html on 25 September 2017. Google Scholar Author, Article, and Disclosure InformationAffiliations: Baltimore, Maryland (D.B.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoDeath and Cardiac Arrest in U.S. Triathlon Participants, 1985 to 2016 Kevin M. Harris , Lawrence L. Creswell , Tammy S. Haas , Taylor Thomas , Monica Tung , Erin Isaacson , Ross F. Garberich , and Barry J. Maron Death and Cardiac Arrest in U.S. Triathlon Participants Kevin M. Harris , Lawrence L. Creswell , and Barry J. Maron Death and Cardiac Arrest in U.S. Triathlon Participants Arthur J. Siegel Metrics Cited byEpidemiological Aspects of Illness and Injury 15 May 2018Volume 168, Issue 10Page: 752KeywordsCardiovascular therapyDisclosureEmotionsExerciseHeartHeart diseasesIschemiaPanic disorderRacial and ethnic issuesSwimming ePublished: 15 May 2018 Issue Published: 15 May 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Validation of a clinical scoring system to predict risk of hepatocellular carcinoma in an ethnically diverse cohort of patients with chronic hepatitis C virus infection
Authors: M.T. Wei, M.H. Le, A. Le, H.N. Trinh, G. Wong, C. Landis, J. Zhang, P. Nguyen, M.-H. Lee, F. Ji, D.H. Lee, E. Ogawa, M. Chang, M. Nguyen
Journal: Journal of Hepatology (2018)
Multimorbidity in Older Adults With Cardiovascular Disease
Authors: Daniel E. Forman, Mathew S. Maurer, Cynthia Boyd, Ralph Brindis, Marcel E. Salive, Frances McFarland Horne, Susan P. Bell, Terry Fulmer, David B. Reuben, Susan Zieman, Michael W. Rich
Journal: Journal of the American College of Cardiology (2018)