tbuckley/cabot-search huggingface dataset:
Association of Intracranial Pressure and Spontaneous Retinal Venous Pulsation
Authors: Linda D’Antona, James A. McHugh, Federico Ricciardi, Lewis W. Thorne, Manjit S. Matharu, Laurence D. Watkins, Ahmed K. Toma, Fion D. Bremner
Journal: JAMA Neurology (2019)

<h3>Importance</h3> A convenient and reliable method for noninvasive intracranial pressure assessments is desirable to reduce the need for invasive procedures (eg, intracranial pressure monitoring and lumbar punctures) and allow clinicians to identify and treat patients with intracranial hypertension in a timely manner. <h3>Objective</h3> To determine whether infrared video assessment of spontaneous retinal venous pulsation is associated with intracranial pressure and is a valid tool to indicate the presence or absence of raised intracranial pressure in patients without papilledema. <h3>Design, Setting, and Participants</h3> A single-center prospective study was conducted at a tertiary referral center between January 2017 and May 2018. Patients consecutively admitted for clinically indicated elective 24-hour invasive intracranial pressure monitoring had ophthalmic review including infrared video recording of their spontaneous venous pulsation. Two neuro-ophthalmologists, who were masked to the intracranial pressure monitoring results, independently graded the spontaneous venous pulsation (grade 0 to 3). Analysis began in June 2018. <h3>Main Outcomes and Measures</h3> The association between simultaneously recorded intracranial pressure and spontaneous venous pulsation (binary variable: present/absent) assessed through retinal infrared video recordings was evaluated using a multiple linear regression model. <h3>Results</h3> Of 105 patients, the mean (SD) age was 39 (14) years, and 79 (75%) were women. The mean (SD) simultaneous intracranial pressure was 1 (5) mm Hg for 91 patients (86.7%) with spontaneous venous pulsations and 13 (14) mm Hg for 14 patients (13.3%) without spontaneous venous pulsations. A multiple linear regression model adjusted for 7 potential confounders confirmed a statistically significant association between intracranial pressure and spontaneous venous pulsation (β = −9.1; 95% CI, −13.7 to −4.6;<i>P</i> &lt; .001; adjusted<i>R</i><sup>2</sup> = 0.42). <h3>Conclusions and Relevance</h3> The absence of spontaneous venous pulsation on retinal infrared video recordings is significantly associated with higher levels of intracranial pressure and should raise the suspicion of intracranial hypertension.
Temporal changes in molecular aerobiome diversity by applying DNA metabarcode sequencing across the pollen season
Authors: B. Campbell, J. Al Kouba, M. Noor, V. Timbrell, E. Gilding, N. Angel, B. Kemish, K. Massel, P. Hugenholz, I. Godwin, J. M. Davies
Journal: Allergy (2019)
Trust’s refusal to allow girl on life support to go to Italy for treatment breaches EU law, court hears
Authors: Clare Dyer
Journal: BMJ (2019)

A London hospital’s refusal to allow a seriously ill 5 year old girl to travel to Italy for treatment is a breach of her right to free movement under European Union law and to religious freedom under the European Convention on Human Rights, the High Court has been told.

Tafida Raqeeb has serious and irreversible brain damage and is on life support at the Royal London Hospital after an arteriovenous malformation rupture in February. Barts Health NHS trust, which runs the Royal London, argues that treatment is futile and that it would be in her best …
Knee osteoarthritis risk in non-industrial societies undergoing an energy balance transition: evidence from the indigenous Tarahumara of Mexico
Authors: Ian J Wallace, David T Felson, Steven Worthington, Jeffrey Duryea, Margaret Clancy, Piran Aliabadi, Geeta N Eick, J Josh Snodgrass, Aaron L Baggish, Daniel E Lieberman
Journal: Annals of the Rheumatic Diseases (2019)

Non-industrial societies with low energy balance levels are expected to be less vulnerable than industrial societies to diseases associated with obesity including knee osteoarthritis. However, as non-industrial societies undergo rapid lifestyle changes that promote positive energy balance, individuals whose metabolisms are adapted to energetic scarcity are encountering greater energy abundance, increasing their propensity to accumulate abdominal adipose tissue and thus potentially their sensitivity to obesity-related diseases.Here, we propose that knee osteoarthritis is one such disease for which susceptibility is amplified by this energy balance transition.Support for our hypothesis comes from comparisons of knee radiographs, knee pain and anthropometry among men aged ≥40 years in two populations: Tarahumara subsistence farmers in Mexico undergoing the energy balance transition and urban Americans from Framingham, Massachusetts.We show that despite having markedly lower obesity levels than the Americans, the Tarahumara appear predisposed to accrue greater abdominal adiposity (ie, larger abdomens) for a given body weight, and are more vulnerable to radiographic and symptomatic knee osteoarthritis at lower levels of body mass index. Also, proportionate increases in abdomen size in the two groups are associated with greater increases in radiographic knee osteoarthritis risk among the Tarahumara than the Americans, implying that the abdominal adipose tissue of the Tarahumara is a more potent stimulus for knee degeneration.Heightened vulnerability to knee osteoarthritis among non-industrial societies experiencing rapid lifestyle changes is a concern that warrants further investigation since such groups represent a large but understudied fraction of the global population.
An Artificial Intelligence Approach in Classifying Acute Myeloid Leukemia and Myelodysplastic Syndrome for Minimal Residual Disease Detection with Post Induction Prognosis Analysis Using Flow Cytometry
Authors: Bor-Sheng Ko, Chi-Cheng Li, Yu-Fen Wang, Jeng-Lin Li, Hsin-An Hou, Pei-Fang Weng, Hwei-Fang Tien, Chi-Chun Lee, Jih-Luh Tang
Journal: Blood (2017)
Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer
Authors: Fan Luo, Min Luo, Qi-Xiang Rong, Hong Zhang, Zhen Chen, Fang Wang, Hong-Yun Zhao, Li-Wu Fu
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> PD-1/PD-L1 blockade has received approval for clinical application due to its encouraging benefit with improving prognosis in selected populations. Unfortunately, the response to immunotherapy for many patients remains unsatisfactory. It remains a great challenge to generate potential combinations that will outperform single agents alone with regard to anti-tumor activity. <h3>Methods</h3> Using NSCLC cell lines and mouse models, we explored the effects of combined niclosamide and PD-L1 blockade on tumor growth and T cell function. Furthermore, we investigated the relationship between PD-L1 and p-STAT3 expression in tumor samples from patients with NSCLC using IHC, as well as their relationship to patient survival. <h3>Results</h3> In vitro, niclosamide, an antihelmintic drug, enhanced the cancer cell lysis mediated by T cells in the presence of PD-L1 blockade. Accordingly, mice treated with niclosamide and PD-L1 antibody showed significant delay in tumor growth and increased survival which were associated with the increase of tumor infiltrating T cells and granzyme B release. Importantly, we found niclosamide could decrease the expression of PD-L1 in both a concentration- and time-dependent manner in NSCLC cells, which was linked to the blockage of p-STAT3 binding to the promoter of PD-L1. <h3>Conclusions</h3> An enhancement of PD-L1 antibody by niclosamide was observed in inhibition of NSCLC growth in vitro and in vivo, which was involved in blockage of p-STAT3 binding to promoter of PD-L1 and finally downregulation of PD-L1 expression. These encourage the combination therapy of niclosamide and PD-1/PD-L1 blockade to be further studied in clinic.
Reply to Maitra and Bhattacharjee: Adherence to the Prevailing Sepsis Definition Is Quintessential to Subphenotype Identification
Authors: Sivasubramanium V. Bhavani, Philip A. Verhoef, Matthew M. Churpek
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

We read the article "Identifying Novel Sepsis Subphenotypes Using Temperature Trajectories" by Bhavani and colleagues (1) with great interest.The authors identified four subphenotypes of patients with sepsis from temperature trajectories and found a significant variability in clinical outcomes and inflammatory markers.However, there are a few concerns that we believe need to be mentioned.The authors included hospitalized patients with infection according to Rhee's criteria and did not adhere to the current Sepsis-3 definition (2) or the previous American College of Chest Physicians/Society of Critical Care Medicine sepsis definition (3).Sepsis-3 defines sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection."We believe that this has incurred a significant bias that may be reflected as lower in-hospital mortality rates in both the derivation and validation cohorts.The authors reported an overall in-hospital mortality of 6% in the derivation cohort and 6.1% in the validation cohort.On the other hand, a U.S. nationwide inpatient database analysis revealed that in-hospital mortality declined from 23.7% to 18.4% between 2007 and 2011 (4).In that study, the authors identified sepsis, severe sepsis, and septic shock according to ICD-9 coding.Significant heterogeneity in the mortality rate among patients with septic shock is already known.We believe that the patients included in this study had "suspected infection" rather than sepsis.As we understand it, the authors used the quick Sequential Organ Failure Assessment (qSOFA) score as an indicator of disease severity; however, qSOFA is known to be inferior to SOFA for predicting in-hospital mortality in patients in both ICU and non-ICU settings (5).Therefore, the role of baseline disease severity as an independent predictor of mortality cannot be ruled out in four temperature trajectory groups when qSOFA is used.
Metabolically healthy obesity: facts and fantasies
Authors: Gordon I. Smith, Bettina Mittendorfer, Samuel Klein
Journal: Journal of Clinical Investigation (2019)

Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered “metabolically healthy.” However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO — specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.
Does distress screening lead to mental health care in older adult surgical patients?
Authors: Kelly Marie Trevino, Christian J. Nelson, Rebecca Saracino, Beatriz Korc-Grodzicki, Saman Sarraf, Armin Shahrokni
Journal: Journal of Clinical Oncology (2019)

11543 Background: Surgery is a notable stressor for older adults with cancer who are often medically complex and frail. The American College of Surgeons Commission on Cancer requires distress screening in accredited cancer care settings. The degree to which distress screening leads to mental health use is unclear. This study examined rates and predictors of post-surgical mental health care in older adults referred for a preoperative evaluation. Methods: Patients aged 75 years or older (n = 1,008) referred to the Geriatrics Service at a comprehensive cancer center were enrolled. Patients underwent elective surgery with a length of stay of 3 days or longer and were followed for at least 30 days after surgery. A comprehensive geriatric assessment (CGA) was administered as part of routine care. Surgical characteristics and post-surgical encounters with social work, psychology, and psychiatry were abstracted from the electronic medical record. Bivariate relationships between demographic and surgical characteristics and the CGA and post-operative receipt of mental health services were examined. Characteristics with significant (p &lt; .01) bivariate relationships were entered into a multivariable regression predicting post-operative mental health service use. Results: One-quarter of the total sample (n = 246, 24.4%) received post-operative mental health services. In multivariable analyses, high distress (Distress Thermometer score≥4; p = .01), poor social support (p = .01), iADL dependence (p = .04), and longer length of stay (p &lt; .001) were associated with receipt of mental health services after controlling for significant sociodemographic and surgical characteristics and CGA variables. Of patients with high distress, poor social support, or iADL dependence, only one-third (29-33%) received mental health care. Conclusions: Distressed older adults and those with low levels of support pre-operatively were more likely to receive mental health services after surgery, controlling for sociodemographic and surgical characteristics. Yet, only one-third of these patients received mental health care. These findings suggest that barriers to translating distress screening into provision of mental health services remain.
IL-1β dominates the promucin secretory cytokine profile in cystic fibrosis
Authors: Gang Chen, Ling Sun, Takafumi Kato, Kenichi Okuda, Mary B. Martino, Aiman Abzhanova, Jennifer M. Lin, Rodney C. Gilmore, Bethany D. Batson, Yvonne K. O’Neal, Allison S. Volmer, Hong Dang, Yangmei Deng, Scott H. Randell, Brian Button, Alessandra Livraghi-Butrico, Mehmet Kesimer, Carla M.P. Ribeiro, Wanda K. O’Neal, Richard C. Boucher
Journal: Journal of Clinical Investigation (2019)

Cystic fibrosis (CF) lung disease is characterized by early and persistent mucus accumulation and neutrophilic inflammation in the distal airways. Identification of the factors in CF mucopurulent secretions that perpetuate CF mucoinflammation may provide strategies for novel CF pharmacotherapies. We show that IL-1β, with IL-1α, dominated the mucin prosecretory activities of supernatants of airway mucopurulent secretions (SAMS). Like SAMS, IL-1β alone induced MUC5B and MUC5AC protein secretion and mucus hyperconcentration in CF human bronchial epithelial (HBE) cells. Mechanistically, IL-1β induced the sterile α motif–pointed domain containing ETS transcription factor (SPDEF) and downstream endoplasmic reticulum to nucleus signaling 2 (ERN2) to upregulate mucin gene expression. Increased mRNA levels of IL1B, SPDEF, and ERN2 were associated with increased MUC5B and MUC5AC expression in the distal airways of excised CF lungs. Administration of an IL-1 receptor antagonist (IL-1Ra) blocked SAMS-induced expression of mucins and proinflammatory mediators in CF HBE cells. In conclusion, IL-1α and IL-1β are upstream components of a signaling pathway, including IL-1R1 and downstream SPDEF and ERN2, that generate a positive feedback cycle capable of producing persistent mucus hyperconcentration and IL-1α and/or IL-1β–mediated neutrophilic inflammation in the absence of infection in CF airways. Targeting this pathway therapeutically may ameliorate mucus obstruction and inflammation-induced structural damage in young CF children.
Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death
Authors: Cristina Basso, Sabino Iliceto, Gaetano Thiene, Martina Perazzolo Marra
Journal: Circulation (2019)

Despite a 2% to 3% prevalence of echocardiographically defined mitral valve prolapse (MVP) in the general population, the actual burden, risk stratification, and treatment of the so-called arrhythmic MVP are unknown. The clinical profile is characterized by a patient, usually female, with mostly bileaflet myxomatous disease, mid-systolic click, repolarization abnormalities in the inferior leads, and complex ventricular arrhythmias with polymorphic/right bundle branch block morphology, without significant regurgitation. Among the various pathophysiologic mechanisms of electrical instability, left ventricular fibrosis in the papillary muscles and inferobasal wall, mitral annulus disjunction, and systolic curling have been recently described by pathological and cardiac magnetic resonance studies in sudden death victims and patients with arrhythmic MVP. In addition, premature ventricular beats arising from the Purkinje tissue as ventricular fibrillation triggers have been documented by electrophysiologic studies in MVP patients with aborted sudden death. The genesis of malignant ventricular arrhythmias in MVP probably recognizes the combination of the substrate (regional myocardial hypertrophy and fibrosis, Purkinje fibers) and the trigger (mechanical stretch) eliciting premature ventricular beats because of a primary morphofunctional abnormality of the mitral valve annulus. The main clinical challenge is how to identify patients with arrhythmic MVP (which imaging technique and in which patient) and how to treat them to prevent sudden death. Thus, there is a necessity for prospective multicenter studies focusing on the prognostic role of cardiac magnetic resonance and electrophysiologic studies and on the therapeutic efficacy of targeted catheter ablation and mitral valve surgery in reducing the risk of life-threatening arrhythmias, as well as the role of implantable cardioverter defibrillators for primary prevention.
Role of mesenchymal stem cells in delivering Newcastle disease virus to glioma cells and glioma stem cells and enhancing the oncolytic effect of the virus by secreting TRAIL.
Authors: Shimon Slavin, Gila Kazimirsky, Amotz Ziv-Av, Chaya Brodie
Journal: Journal of Clinical Oncology (2013)

3100 Background: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and oncolytic by induction of apoptosis. Preclinical and clinical studies in patients with glioblastoma (GBM) using NDV demonstrated occasional clinical benefits with no major side effects. Limitations to the use of NDV as virotherapy of GBM is the inefficient delivery into cancer cells in the brain. Methods: Mesenchymal stromal cells (MSCs) can migrate towards cancer cells. We examined potential delivery of oncolytic effect of NDV (MTH-68/H) against glioma cell lines and glioma stem cells (GSCs) and the ability of MSCs to deliver NDV to glioma cells and GSCs in culture. Results: NDV induced a dose-dependent cell death in the glioma cells U87, A172 and U251 with maximal effects at 10 MOI. In contrast, we found only small level of apoptosis or changes in self-renewal in three GSCs infected with NDV. We found that MSCs derived from bone marrow, adipose tissue and cord were successfully infected by NDV and were able to deliver the virus to co-cultured glioma cells and GSCs. In addition, treatment of glioma cells and GSCs with culture supernatant of infected MSCs increase apoptosis of glioma cells as compared to the effect of direct infection of glioma cells. Moreover, the culture supernatants of the infected MSCs induced cell death in GSCs that were resistant to the oncolytic effect of NDV, suggesting that factor(s) secreted by the infected MSCs sensitized the glioma cells and GSCs to the cytotoxic effects of NDV. Using antibody array and ELISA we identified TRAIL as the factor secreted from infected MSCs. Indeed, treatment of infected glioma cells with TRAIL increased the cytotoxic effect of NDV and sensitized GSCs to the oncolytic effects of NDV. Conclusions: MSCs can be employed to deliver NDV to GBM. In addition, MSCs can also sensitize glioma cells and GSCs to oncolysis by NDV. Considering the resistance of GSCs to chemotherapy and radiation therapy, treatment of GBM with MSC-mediated targeted oncolytic NDV may provide a new clinical tool for treatment of GBM and eradication of GSCs.
Allosteric modulation of G protein‐coupled receptors by amiloride and its derivatives. Perspectives for drug discovery?
Authors: Arnault Massink, Tasia Amelia, Alex Karamychev, Adriaan P. IJzerman
Journal: Medicinal Research Reviews (2019)

Abstract The function of G protein‐coupled receptors (GPCRs) can be modulated by compounds that bind to other sites than the endogenous orthosteric binding site, so‐called allosteric sites. Structure elucidation of a number of GPCRs has revealed the presence of a sodium ion bound in a conserved allosteric site. The small molecule amiloride and analogs thereof have been proposed to bind in this same sodium ion site. Hence, this review seeks to summarize and reflect on the current knowledge of allosteric effects by amiloride and its analogs on GPCRs. Amiloride is known to modulate adenosine, adrenergic, dopamine, chemokine, muscarinic, serotonin, gonadotropin‐releasing hormone, GABA B , and taste receptors. Amiloride analogs with lipophilic substituents tend to be more potent modulators than amiloride itself. Adenosine, α‐adrenergic and dopamine receptors are most strongly modulated by amiloride analogs. In addition, for a few GPCRs, more than one binding site for amiloride has been postulated. Interestingly, the nature of the allosteric effect of amiloride and derivatives varies considerably between GPCRs, with both negative and positive allosteric modulation occurring. Since the sodium ion binding site is strongly conserved among class A GPCRs it is to be expected that amiloride also binds to class A GPCRs not evaluated yet. Investigating this typical amiloride‐GPCR interaction further may yield general insight in the allosteric mechanisms of GPCR ligand binding and function, and possibly provide new opportunities for drug discovery.