Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes

The Properties of the Radio-Selected 1Jy Sample of BL Lacertae Objects

We present new optical and near-IR spectroscopy as well as new high dynamic range, arcsecond-resolution VLA radio maps of BL Lacs from the complete radio-selected "1 Jansky" (1Jy) sample (RBLs) for which such data were not previously available. Unlike BL Lacs from the complete X-ray-selected Einstein Medium Sensitivity Survey (EMSS) sample (XBLs), most RBLs possess weak but moderately luminous emission lines. And whereas nearly all XBLs have extended power levels consistent with FR-1s, more than half of the RBLs have extended radio power levels too luminous to be beamed FR-1 radio galaxies. In fact, we find evidence for and examples of three distinct mechanisms for creating the BL Lac phenomenon in the 1Jy sample: beamed FR-1s, beamed FR-2s and possibly a few gravitationally-lensed quasars. The v/v_max determined for the 1Jy sample is 0.614+/-0.047, which is markedly different from the negative evolution seen in the EMSS and other XBL samples. A correlation between logarithmic X-ray to radio flux ratio and v/v_max is observed across the EMSS and 1Jy samples, from negative evolution in the more extreme XBLs to positive evolution in the more extreme RBLs. There is evidence that the selection criteria chosen by Stickel et al. eliminates some BL Lac objects from the 1Jy sample, although how many is unknown. And several objects currently in the sample have exhibited strong emission lines in one or more epochs, suggesting they should be reclassified as FSRQs. However these selection effects cannot account for the observed discrepancy in XBL and RBL properties. From these observational properties we conclude that RBLs and XBLs cannot be related by viewing angle alone, and that RBLs are more closely related to FSRQs.Comment: 29 pages, 47 figures, accepted A

Characterization of indeterminate breast lesions on B-mode ultrasound using automated machine learning models

Purpose: While mammography has excellent sensitivity for the detection of breast lesions, its specificity is limited. Adjunct screening with ultrasound may partially alleviate this issue, but also increases false positives, resulting in unnecessary biopsies. This study investigated the use of Google AutoML Vision (Mountain View, CA), a commercially available machine learning service, to both identify and characterize indeterminate breast lesions on ultrasound. Methods: B-mode images from 253 independent cases of indeterminate breast lesions scheduled for core biopsy were used for model creation and validation. The performances of two sub-models from AutoML Vision, the image classification model and object detection model were evaluated, while also investigating training strategies to enhance model performances. Pathology from the patient’s biopsy were used as a reference standard. Results: The image classification models trained under different conditions demonstrated areas under the precision recall curve (AUC) ranging from 0.85 to 0.96 during internal validation. Once deployed, the model with highest internal performance demonstrated a sensitivity of 100% (95% confidence interval (CI) of 73.5-100%), specificity of 83.3% (CI=51.6-97.9%), positive predictive value (PPV) of 85.7% (CI=62.9-95.5%), and negative predictive value (NPV) of 100% (CI non-evaluable) in an independent dataset. The object detection model demonstrated lower performance internally during development (AUC=0.67) and during prediction in the independent dataset (sensitivity=75.0% (CI=42.8-94.5), specificity=80.0% (CI=51.9-95.7), PPV=75.0% (CI=50.8-90.0), NPV=80.0% (CI=59.3-91.7%)), but was able to demonstrate the location of the lesion within the image. Conclusions: Two models appear to be useful tools for identifying and classifying suspicious areas on B-mode images of indeterminate breast lesions

The Lunacy Commission.

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Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome

Introduction: Intravenous (IV) fluids may be associated with complications not often attributed to fluid type. Fluids with high chloride concentrations such as 0.9 % saline have been associated with adverse outcomes in surgery and critical care. Understanding the association between fluid type and outcomes in general hospitalized patients may inform selection of fluid type in clinical practice. We sought to determine if the type of IV fluid administered to patients with systemic inflammatory response syndrome (SIRS) is associated with outcome. Methods: This was a propensity-matched cohort study in hospitalized patients receiving at least 500 mL IV crystalloid within 48 hours of SIRS. Patient data was extracted from a large multi-hospital electronic health record database between January 1, 2009, and March 31, 2013. The primary outcome was in-hospital mortality. Secondary outcomes included length of stay, readmission, and complications measured by ICD-9 coding and clinical definitions. Outcomes were adjusted for illness severity using the Acute Physiology Score. Of the 91,069 patients meeting inclusion criteria, 89,363 (98 %) received 0.9 % saline whereas 1706 (2 %) received a calcium-free balanced solution as the primary fluid. Results: There were 3116 well-matched patients, 1558 in each cohort. In comparison with the calcium-free balanced cohort, the saline cohort experienced greater in-hospital mortality (3.27 % vs. 1.03 %, P <0.001), length of stay (4.87 vs. 4.38 days, P = 0.016), frequency of readmission at 60 (13.54 vs. 10.91, P = 0.025) and 90 days (16.56 vs. 12.58, P = 0.002) and frequency of cardiac, infectious, and coagulopathy complications (all P <0.002). Outcomes were defined by administrative coding and clinically were internally consistent. Patients in the saline cohort received more chloride and had electrolyte abnormalities requiring replacement more frequently (P <0.001). No differences were found in acute renal failure. Conclusions: In this large electronic health record, the predominant use of 0.9 % saline in patients with SIRS was associated with significantly greater morbidity and mortality compared with predominant use of balanced fluids. The signal is consistent with that reported previously in perioperative and critical care patients. Given the large population of hospitalized patients receiving IV fluids, these differences may confer treatment implications and warrant corroboration via large clinical trials. Trial registration: NCT02083198 clinicaltrials.gov; March 5, 201

Freshwater invertebrate responses to fine sediment stress: a multi-continent perspective

Excessive fine sediment (particles <2 mm) deposition in freshwater systems is a pervasive stressor worldwide. However, understanding of ecological response to excess fine sediment in river systems at the global scale is limited. Here, we aim to address whether there is a consistent response to increasing levels of deposited fine sediment by freshwater invertebrates across multiple geographic regions (Australia, Brazil, New Zealand, and the UK). Results indicate ecological responses are not globally consistent and are instead dependent on both the region and the facet of invertebrate diversity considered, i.e., taxonomic or functional trait structure. Invertebrate communities of Australia were most sensitive to deposited fine sediment, with the greatest rate of change in communities occurring when fine sediment cover was low (below 25% of the reach). Communities in the UK displayed greater tolerance with most compositional change occurring between 30-60% cover. In both New Zealand and Brazil, which included the most heavily sedimented sampled streams, the communities were more tolerant or demonstrated ambiguous responses, likely due to historic environmental filtering of invertebrate communities. We conclude that ecological responses to fine sediment are not generalisable globally and are dependent on landscape filters with regional context and historic land management playing important roles

Models of classroom assessment for course-based research experiences

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment—(1) Assessing Laboratory Work and Scientific Thinking; (2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; (3) Appraising Forms of Scientific Communication; and (4) Metacognition of Learning—along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students’ ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education

Prehospital transdermal glyceryl trinitrate in patients with ultra-acute presumed stroke (RIGHT-2): an ambulance-based, randomised, sham-controlled, blinded, phase 3 trial

Background High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset. Methods We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053. Findings Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants’ systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (p<0·0001), and diastolic blood pressure was lowered by 2·6 mm Hg (p=0·0026) at hospital admission. We found no difference in mRS between the groups in participants with a final diagnosis of stroke or transient ischaemic stroke (cohort 1): 3 (IQR 2–5; n=420) in the GTN group versus 3 (2–5; n=408) in the sham group, adjusted common odds ratio for poor outcome 1·25 (95% CI 0·97–1·60; p=0·083); we also found no difference in mRS between all patients (cohort 2: 3 [2–5]; n=544, in the GTN group vs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups. Interpretation Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultraacute prehospital setting. Funding British Heart Foundation

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes