tbuckley/cabot-search huggingface dataset:
Phase II trial of pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC).
Authors: Robin Kate Kelley, Emily Mitchell, Spencer Behr, Jimmy Hwang, Bridget Keenan, Alexander Cheung, John Dozier Gordan, Andrew H. Ko, Pelin Cinar, Chloe Evelyn Atreya, Katherine Van Loon, Thomas Weber, Zoe Ngo, Zoe E. Quandt, Chienying Liu, Alan P. Venook, Lawrence Fong
Journal: Journal of Clinical Oncology (2018)

386 Background: The efficacy of immune checkpoint inhibition (CPI) has not been established in ABC. GM-CSF modulates immune effector cells and has demonstrated safety and improved survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial aims to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Design: Simon’s 2-stage. Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior CPI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 Safety Cohort) or in cycles 1 and 2 (Stage 2). Endpoints: 1 ◦ : Progression-free survival at 6 months (PFS6) with H 0 25% vs. H 1 50%. Key 2 ◦ : Safety, overall response rate (ORR) and duration (DOR), OS, PD-L1 expression. Exploratory: PBMC and tumor immune cell profiles, tumor genotype, microsatellite (in)stability (MSI or MSS). Results: Accrual has completed with 27 patients (pts) enrolled 5/2016-6/2017: F/M 13/14; median age 61 (range 37-77); intrahepatic 19 (70%), extrahepatic 7 (26%), mixed 1 (4%) cholangiocarcinoma; stage IVA/B 85%, II/III 15%; median prior therapies 2 (range 1-6). Adverse events (AE): Related grade(Gr) ≥3 AE occurred in 4/27 (15%) pts including immune-related (ir)AE of Gr4 diabetes mellitus and Gr3 thrombocytopenia in 1 pt each. Gr≤2 irAE in ≥5% were: arthralgia (33%), dry eye/mouth (15%), hyperthyroid/thyroiditis (15%), hypothyroid (15%), neuropathy (11%), rash (11%), and adrenal insufficiency (7%). Steroids were required in 3/27 (11%) pts. Disposition: 19 pts removed for PD, 1 for Gr2 irAE; 7 pts remain active on treatment. Median time on treatment: 6 cycles (range 2-22+). Best response by RECIST 1.1: Partial response (PR) in 5/24 (21%) evaluable pts (1 MSI, 4 MSS); minor regression and ≥50% CA 19-9 decline in 2 additional MSS pts for 11+ and 16+ months. PBMC analyses show changes in expression of activating and inhibitory markers including PD-1 on various immune cell populations. Conclusions: PEM plus induction GM-CSF is safe and tolerable in ABC. Durable radiographic and tumor marker responses including MSS pts warrant further study. PFS6, OS, and correlative analyses are ongoing. Clinical trial information: NCT02703714.
Circuit dissection of the role of somatostatin in itch and pain
Authors: Jing Huang, Erika Polgár, Hans Jürgen Solinski, Santosh K. Mishra, Pang-Yen Tseng, Noboru Iwagaki, Kieran A. Boyle, Allen C. Dickie, Mette C. Kriegbaum, Hendrik Wildner, Hanns Ulrich Zeilhofer, Masahiko Watanabe, John S. Riddell, Andrew J. Todd, Mark A. Hoon
Journal: Nature Neuroscience (2018)
Development of White Matter Circuitry in Infants With Fragile X Syndrome
Authors: Meghan R. Swanson, Jason J. Wolff, Mark D. Shen, Martin Styner, Annette Estes, Guido Gerig, Robert C. McKinstry, Kelly N. Botteron, Joseph Piven, Heather C. Hazlett
Journal: JAMA Psychiatry (2018)

<h3>Importance</h3> Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. <h3>Objective</h3> To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. <h3>Design, Setting, and Participants</h3> Longitudinal behavioral and brain imaging data were collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. <h3>Main Outcomes and Measures</h3> Nineteen major white matter pathways were defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. <h3>Results</h3> There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate,<i>F</i> = 10.06; false discovery rate–corrected<i>P</i> = .03; right uncinate,<i>F</i> = 21.8;<i>P</i> = .004). <h3>Conclusions and Relevance</h3> The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.
Antidepressants might work for people with major depression: where do we go from here?
Authors: Andrea Cipriani, Georgia Salanti, Toshi A Furukawa, Matthias Egger, Stefan Leucht, Henricus G Ruhe, Erick H Turner, Lauren Z Atkinson, Anna Chaimani, Julian P T Higgins, Yusuke Ogawa, Nozomi Takeshima, Yu Hayasaka, Hissei Imai, Kiyomi Shinohara, Aran Tajika, John P A Ioannidis, John R Geddes
Journal: The Lancet Psychiatry (2018)
Humanized mouse model of Rasmussen’s encephalitis supports the immune-mediated hypothesis
Authors: Hania Kebir, Lionel Carmant, François Fontaine, Kathie Béland, Ciprian M. Bosoi, Nathalie T. Sanon, Jorge I. Alvarez, Sébastien Desgent, Camille L. Pittet, David Hébert, Marie-Josée Langlois, Rose-Marie Rébillard, Dang K. Nguyen, Cécile Cieuta-Walti, Gregory L. Holmes, Howard P. Goodkin, John R. Mytinger, Mary B. Connolly, Alexandre Prat, Elie Haddad
Journal: Journal of Clinical Investigation (2018)

Rasmussen's encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-γ– and granzyme B–expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of α4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn's disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics.
Association of Muscle and Adiposity Measured by Computed Tomography With Survival in Patients With Nonmetastatic Breast Cancer
Authors: Bette J. Caan, Elizabeth M. Cespedes Feliciano, Carla M. Prado, Stacey Alexeeff, Candyce H. Kroenke, Patrick Bradshaw, Charles P. Quesenberry, Erin K. Weltzien, Adrienne L. Castillo, Taiwo A. Olobatuyi, Wendy Y. Chen
Journal: JAMA Oncology (2018)

Sarcopenia (low muscle mass), poor muscle quality (low muscle radiodensity), and excess adiposity derived from computed tomography (CT) has been related to higher mortality in patients with metastatic breast cancer, but the association with prognosis in patients with nonmetastatic breast cancer is unknown.To evaluate associations of all 3 body composition measures, derived from clinically acquired CT at diagnosis, with overall mortality in nonmetastatic breast cancer.This observational study included 3241 women from Kaiser Permanente of Northern California and Dana Farber Cancer Institute diagnosed from January 2000 to December 2013 with stages II or III breast cancer. We calculated hazard ratios (HRs) to evaluate the associations of all-cause mortality with sarcopenia, low muscle radiodensity, and total adipose tissue (TAT). Models were adjusted for sociodemographics, tumor characteristics, treatment, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and other body composition measures. We also evaluated the cross-classification of categories of sarcopenia (yes/no) and tertiles of TAT, with outcomes.Overall survival time and all-cause mortality.Median (range) age of 3241 women included in this study was 54 (18-80) years, and median follow-up was 6.0 years; 1086 patients (34%) presented with sarcopenia, and 1199 patients (37%) had low muscle radiodensity. Among patients with nonmetastatic breast cancer, those with sarcopenia showed higher overall mortality (HR, 1.41; 95% CI, 1.18-1.69) compared with those without sarcopenia. Patients in the highest tertile of TAT also showed higher overall mortality (HR, 1.35; 95% CI, 1.08-1.69) compared with those in the lowest tertile. Low radiodensity was not associated with survival. In analyses of sarcopenia and TAT, highest mortality was seen in patients with sarcopenia and high TAT (HR, 1.89; 95% CI, 1.30-2.73); BMI alone was not significantly related to overall mortality and did not appropriately identify patients at risk of death owing to their body composition.Sarcopenia is underrecognized in nonmetastatic breast cancer and occurs in over one-third of newly diagnosed patients. Measures of both sarcopenia and adiposity from clinically acquired CT scans in nonmetastatic patients provide significant prognostic information that outperform BMI and will help to guide interventions to optimize survival outcomes.
Open‐Label, Non‐Mandatory Transitioning From Originator Etanercept to Biosimilar <scp>SB</scp>4
Authors: Lieke Tweehuysen, Victor J. B. Huiskes, Bart J. F van den Bemt, Johanna E. Vriezekolk, Steven Teerenstra, Frank H. J. van den Hoogen, Cornelia H. van den Ende, Alfons A. den Broeder
Journal: Arthritis & Rheumatology (2018)

Objective To evaluate the effects of non‐mandatory transitioning from the originator biologic drug etanercept ( ETN ) to its biosimilar, SB 4, on drug survival and effectiveness in a controlled cohort study of patients with an inflammatory rheumatic disease. Methods In 2016, 642 patients were asked to transition their treatment from originator ETN to biosimilar SB 4 by a structured communication strategy with opt‐out option. Patients who consented to switch to SB 4 were considered eligible for inclusion in the transition cohort, while patients being treated with originator ETN in 2014 were recruited as the historical cohort. Drug survival was compared between the 2 cohorts using Cox regression analyses, which were adjusted for age, sex, diagnosis, ETN treatment duration, ETN dose interval, conventional synthetic disease‐modifying antirheumatic drug usage, and C‐reactive protein ( CRP ) level, with a robust variance estimator applied to account for repeated subjects (i.e., patients who were included in both the transition cohort and the historical cohort). Adjusted differences in the 6‐month change in CRP level, Disease Activity Score in 28 joints using CRP level ( DAS 28‐ CRP ), and Bath Ankylosing Spondylitis Disease Activity Index were also assessed. Results Of the 642 ETN ‐treated patients, 635 (99%) agreed to transition from originator ETN to biosimilar SB 4, of whom 625 patients (433 with rheumatoid arthritis, 128 with psoriatic arthritis, and 64 with ankylosing spondylitis) were included in the transition cohort, and 600 ETN ‐treated patients from 2014 were included in the historical cohort. The crude treatment persistence rate for biosimilar SB 4 over 6 months was 90% (95% confidence interval [95% CI ] 88–93%), compared to a 6‐month treatment persistence rate of 92% (95% CI 90–94%) for originator ETN . Patients in the transition cohort, compared to the historical cohort, had a statistically significantly higher relative risk of treatment discontinuation (adjusted hazard ratio 1.57, 95% CI 1.05–2.36) and showed smaller decreases in the CRP level (adjusted difference 1.8, 95% CI 0.3–3.2) and DAS 28‐ CRP (adjusted difference 0.15, 95% CI 0.05–0.25) over 6 months. Conclusion Non‐mandatory transitioning from originator ETN to biosimilar SB 4 using a specifically designed communication strategy resulted in a slightly lower 6‐month treatment persistence rate and smaller decreases in disease activity in the transition cohort compared to the historical cohort, but these differences were not considered clinically relevant.
Patient and Family Engagement in the ICU. Untapped Opportunities and Underrecognized Challenges
Authors: Karen E. A. Burns, Cheryl Misak, Margaret Herridge, Maureen O. Meade, Simon Oczkowski
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The call for meaningful patient and family engagement in health care and research is gaining impetus. Healthcare institutions and research funding agencies increasingly encourage clinicians and researchers to work actively with patients and their families to advance clinical care and research. Engagement is increasingly mandated by healthcare organizations and is becoming a prerequisite for research funding. In this article, we review the rationale and the current state of patient and family engagement in patient care and research in the ICU. We identify opportunities to strengthen engagement in patient care by promoting greater patient and family involvement in care delivery and supporting their participation in shared decision-making. We also identify challenges related to patient willingness to engage, barriers to participation, participant risks, and participant expectations. To advance engagement, clinicians and researchers can develop the science behind engagement in the ICU context and demonstrate its impact on patient- and process-related outcomes. In addition, we provide practical guidance on how to engage, highlight features of successful engagement strategies, and identify areas for future research. At present, enormous opportunities remain to enhance engagement across the continuum of ICU care and research.
Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2–3 trial
Authors: Michele Reni, Gianpaolo Balzano, Silvia Zanon, Alessandro Zerbi, Lorenza Rimassa, Renato Castoldi, Domenico Pinelli, Stefania Mosconi, Claudio Doglioni, Marta Chiaravalli, Chiara Pircher, Paolo Giorgio Arcidiacono, Valter Torri, Paola Maggiora, Domenica Ceraulo, Massimo Falconi, Luca Gianni
Journal: The Lancet. Gastroenterology & hepatology (2018)
In situ formation of interpenetrating polymer network using sequential thermal and click crosslinking for enhanced retention of transplanted cells
Authors: Hamid Sadeghi Abandansari, Mohammad Hossein Ghanian, Fahimeh Varzideh, Elena Mahmoudi, Sarah Rajabi, Payam Taheri, Mohammad Reza Nabid, Hossein Baharvand
Journal: Biomaterials (2018)
Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response
Authors: Daniela Barbieri, Emilie Elvira-Matelot, Yanis Pelinski, Laetitia Genève, Bérengère de Laval, Gayathri Yogarajah, Christian Pecquet, Stefan N. Constantinescu, Françoise Porteu
Journal: The Journal of Experimental Medicine (2018)

Maintenance of genomic integrity is crucial for the preservation of hematopoietic stem cell (HSC) potential. Retrotransposons, spreading in the genome through an RNA intermediate, have been associated with loss of self-renewal, aging, and DNA damage. However, their role in HSCs has not been addressed. Here, we show that mouse HSCs express various retroelements (REs), including long interspersed element-1 (L1) recent family members that further increase upon irradiation. Using mice expressing an engineered human L1 retrotransposition reporter cassette and reverse transcription inhibitors, we demonstrate that L1 retransposition occurs in vivo and is involved in irradiation-induced persistent γH2AX foci and HSC loss of function. Thus, RE represents an important intrinsic HSC threat. Furthermore, we show that RE activity is restrained by thrombopoietin, a critical HSC maintenance factor, through its ability to promote a potent interferon-like, antiviral gene response in HSCs. This uncovers a novel mechanism allowing HSCs to minimize irradiation-induced injury and reinforces the links between DNA damage, REs, and antiviral immunity.
4-Year Follow-up in a Child with a Total Autologous Tracheal Replacement
Authors: Frédéric Kolb, François Simon, Régis Gaudin, Briac Thierry, Sacha Mussot, Laurent Dupic, Jean-Louis Coste, Nicolas Leboulanger, Françoise Denoyelle, Vincent Couloigner, Erea-Noël Garabedian
Journal: New England Journal of Medicine (2018)

Autologous Complete Tracheal Replacement Management of tracheal stenosis in a child is complex. This letter describes the 4-year follow-up of a child who underwent an autologous complete tracheal replacement.
‘Malignant’ pleural effusion with abdominal gossypiboma
Authors: Tao Fan, Wei Wang, Xiaobo Guo, Qing Geng
Journal: Thorax (2018)

Following a 15-day history of cough with associated breathlessness, a 50-year-old woman presented with bilateral pleural effusions and a pericardial effusion. Her medical history included removal of an appendiceal cyst and a hysteromyoma resection 12 years previously. There was no cardiac or respiratory history. Physical examination revealed decreased breath sounds bilaterally with distant heart sounds heard. Pleural fluid demonstrated high levels of CA125 (2909.70 U/mL; reference range, 3.6–68.6 U/mL), cytokeratin fragment (CYFRA) (724.00 ng/mL; range, 0–3.3 ng/mL), squamous cell carcinoma antigen (SCC) (37.47 ng/mL; range, 0–1.5 ng/mL) and neuron specific enolase (NSE) (31.94 ng/mL; range, 0–16.3 ng/mL). Serum samples demonstrated high levels of CA125 (227.60 U/mL; range, 3.6–68.6 U/mL), CYFRA (6.79 ng/mL; …
Do shamans violate notions of humanness?
Authors: Nick Haslam
Journal: Behavioral and Brain Sciences (2018)

Singh proposes that shamans violate notions of humanness in patterned ways that signal supernatural capacities. I argue that his account, based on a notion of humanness that contrasts humans with non-human animals, does not capture people's understandings of supernatural beings. Shamanic behavior may simply violate human norms in unstructured, improvised ways rather than contrast with a coherent concept of humanness.
Distal versus proximal intestinal short-chain fatty acid release in man
Authors: Evelien PJG Neis, Hans MH van Eijk, Kaatje Lenaerts, Steven WM Olde Damink, Ellen E Blaak, Cornelis HC Dejong, Sander S Rensen
Journal: Gut (2018)

Several recent studies published in Gut highlight the potential of prebiotics and short-chain fatty acids (SCFAs) to improve obesity and its associated metabolic disorders. Catry and colleagues1 demonstrated that inulin-type fructans improve endothelial dysfunction, and Roager et al 2 showed that a whole grain-rich diet reduced body weight and inflammation. Li et al 3 reported that butyrate administration reduced appetite and activated brown adipose tissue in mice, and Chambers and colleagues4 showed that targeted propionate delivery to the human colon reduced energy intake and body weight gain.

In light of these important effects of SCFA, insight into their fate after bacterial production and/or intestinal absorption will help to improve the development of nutritional strategies aiming at modulation of intestinal SCFA. We addressed this issue by assessing SCFA release in the proximal intestines (jejunum, ileum and proximal colon) versus the distal intestines (descending colon, sigmoid and rectum) in man. Blood was simultaneously sampled from the portal vein, hepatic vein, superior mesenteric vein (SMV; draining the proximal intestines), inferior mesenteric vein (IMV; draining the distal intestines) …
Pain-Free Blood Glucose Monitoring Using Wearable Sensors: Recent Advancements and Future Prospects
Authors: Sarah Ali Siddiqui, Yuan Zhang, Jaime Lloret, Houbing Song, Zoran Obradovic
Journal: IEEE Reviews in Biomedical Engineering (2018)

Keeping track of blood glucose levels non-invasively is now possible due to diverse breakthroughs in wearable sensors technology coupled with advanced biomedical signal processing. However, each user might have different requirements and priorities when it comes to selecting a self-monitoring solution. After extensive research and careful selection, we have presented a comprehensive survey on noninvasive/pain-free blood glucose monitoring methods from the recent five years (2012–2016). Several techniques, from bioinformatics, computer science, chemical engineering, microwave technology, etc., are discussed in order to cover a wide variety of solutions available for different scales and preferences. We categorize the noninvasive techniques into nonsample- and sample-based techniques, which we further grouped into optical, nonoptical, intermittent, and continuous. The devices manufactured or being manufactured for noninvasive monitoring are also compared in this paper. These techniques are then analyzed based on certain constraints, which include time efficiency, comfort, cost, portability, power consumption, etc., a user might experience. Recalibration, time, and power efficiency are the biggest challenges that require further research in order to satisfy a large number of users. In order to solve these challenges, artificial intelligence (AI) has been employed by many researchers. AI-based estimation and decision models hold the future of noninvasive glucose monitoring in terms of accuracy, cost effectiveness, portability, efficiency, etc. The significance of this paper is twofold: first, to bridge the gap between IT and medical field; and second, to bridge the gap between end users and the solutions (hardware and software).
GPs retain power to prescribe over-the-counter medicines
Authors: Adrian O’Dowd
Journal: BMJ (2018)

GPs in England will still be able to use their judgment to prescribe over-the-counter medicines to patients in some circumstances, after a national review of prescribing policy that will clamp down on many treatments.

In new guidance,1 NHS England said that it plans to release almost £100m (€115m; $140m) for frontline care each year by curbing prescriptions for “over-the-counter” medicines designed for minor, short term conditions.

The guidance, issued to clinical commissioning groups (CCGs), details how CCGs should seek to restrict prescribing of over-the-counter medicines for eight self limiting conditions and 27 minor ailments. These include acute sore throat, conjunctivitis, haemorrhoids, dandruff, diarrhoea in adults, indigestion/heartburn, infrequent migraine, insect bites/stings, mild acne, …