bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defining high probability when making a diagnosis of asthma in primary care: mixed-methods consensus workshop
Authors: Daines Luke , Lewis Steff , Schneider Antonius , Sheikh Aziz , Pinnock Hilary 
Published: April 2020

ObjectiveMaking the diagnosis of asthma is challenging. Guidelines recommend that clinicians identify a group at ‘high probability’ of asthma. High probability, however, is not numerically defined giving rise to uncertainty. The aim of this work was to build consensus on what constitutes a high probability of asthma in primary care. High probability was defined as the probability threshold at which there is enough information to make a firm diagnosis of asthma, and a subsequent negative test would not alter that opinion (assumed to be a false negative).DesignMixed-methods study.SettingA consensus workshop using modified nominal group technique was held during an international respiratory conference.ParticipantsInternational conference attendees eligible if they had knowledge/experience of working in primary care, respiratory medicine and spoke English.MethodsParticipants took part in facilitated discussions and voted over three rounds on what constituted a high probability of asthma diagnosis. The workshop was audio-recorded, transcribed and qualitatively analysed.ResultsBased on final votes, the mean value for a high probability of asthma in primary care was 75% (SD 7.6), representing a perceived trade-off between limiting the number of false positives (more likely if a lower threshold was used) and pragmatism on the basis that first-line preventive therapies (ie, low-dose inhaled corticosteroids) are relatively low risk. The need to review response to treatment was strongly emphasised for detecting non-responders and reviewing the diagnosis.ConclusionA consensus probability of 75% was the threshold at which the primary care participants in this workshop felt confident to establish the diagnosis of asthma, albeit with the caveat that a review of treatment response was essential. Contextual factors, including availability and timing of tests and the ease with which patients could be reviewed, influenced participants’ decision making.
ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy
Authors: Lopes Jared E , Fisher Jan L , Flick Heather L , Wang Chunhua , Sun Lei , Ernstoff Marc S , Alvarez Juan C , Losey Heather C 
Published: April 2020

BackgroundInterleukin-2 (IL-2) plays a pivotal role in immune homeostasis due to its ability to stimulate numerous lymphocyte subsets including natural killer (NK) cells, effector CD4+and CD8+T cells, and regulatory T cells (Tregs). Low concentrations of IL-2 induce signaling through the high-affinity IL-2 receptor (IL-2R) comprised of IL-2Rα, IL-2Rβ, and common γ chain (γc), preferentially expressed on Tregs. Higher concentrations of IL-2 are necessary to induce signaling through the intermediate-affinity IL-2R, composed of IL-2Rβ and γc, expressed on memory CD8+T cells and NK cells. Recombinant human IL-2 (rhIL-2) is approved for treatment of metastatic melanoma and renal cell carcinoma (RCC), but adverse events including capillary leak syndrome, potentially mediated through interaction with the high-affinity IL-2R, limit its therapeutic use. Furthermore, antitumor efficacy of IL-2 may also be limited by preferential expansion of immunosuppressive Tregs. ALKS 4230 is an engineered fusion protein comprised of a circularly-permuted IL-2 with the extracellular domain of IL-2Rα, designed to selectively activate effector lymphocytes bearing the intermediate-affinity IL-2R.ResultsALKS 4230 was equipotent to rhIL-2 in activating human cells bearing the intermediate-affinity IL-2R, and less potent than rhIL-2 on cells bearing the high-affinity IL-2R. As observed in vitro with primary human cells from healthy donors and advanced cancer patients, ALKS 4230 induced greater activation and expansion of NK cells with reduced expansion of Tregsrelative to rhIL-2. Similarly, in mice, ALKS 4230 treatment stimulated greater expansion of NK cells and memory-phenotype CD8+T cells at doses that did not expand or activate Tregs. ALKS 4230 treatment induced significantly lower levels of proinflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, and interferon gamma relative to rhIL-2. Furthermore, ALKS 4230 exhibited superior antitumor efficacy in the mouse B16F10 lung tumor model, where ALKS 4230 could be administered via multiple routes of administration and dosing schedules while achieving equivalent antitumor efficacy.ConclusionsALKS 4230 exhibited enhanced pharmacokinetic and selective pharmacodynamic properties resulting in both improved antitumor efficacy and lower indices of toxicity relative to rhIL-2 in mice. These data highlight the potential of ALKS 4230 as a novel cancer immunotherapy, and as such, the molecule is being evaluated clinically.
Surface flow modification of aerofoils for automotive racing car applications
Authors: Allarton Richard , Yao Jun , Clifford Tyler , Hitchborn Benjamin , Parker Liam J , Shaw Joshua 
Published: April 2020

An aerofoil commonly used in aerospace engineering to produce lift is also employed in the motor sport industry to produce downforce for improving traction during cornering. This paper investigates aerofoil surface modification through ‘golf ball dimpling’, used to reduce flow separation behind a golf ball. The studies of other researchers have shown that this type of design can have a positive effect on improving aerofoil performance. However, no optimization information of dimple sizing is given in literature. Therefore, three types of dimpling sized at 5, 10 and 15 mm are applied to the surface of a NACA 6615 wing at 25% chord length from the leading edge in this study using Computational Fluid Dynamics (CFD) as an initial design process. Then a physical model, made through 3D printing additive manufacturing (AM), is tested at angles of attack (AoA) ranging from [Formula: see text] to [Formula: see text] and wind speed up to 30 m/s in a subsonic wind tunnel. Experimental and CFD results show that the smallest dimple size provides the most significant increase on lift to drag ratio at high AoA above [Formula: see text]. This ratio increases further with the wind speed, indicating that a high AoA wing favors down force to improve drag reduction performance.
Exploration on application of dredging thermal protection in the leading edge of the wing
Authors: Zhu Xiao-Jun , Li Feng 
Published: April 2020

Aiming at the severe aerodynamic heating problem in the leading edge of the hypersonic vehicle, in order to ensure the sharp shape of the leading edge of the wing, a dredging thermal protection structure is proposed, and the built-in high-temperature heat pipe structure is used to provide thermal protection for the leading edge of the wing. By means of numerical simulation and arc wind tunnel test, the dredging thermal protection structure of the leading edge of the wing is analyzed, and the thermal protection effect of the built-in high-temperature heat pipe is obtained. The numerical results show that under certain thermal conditions, the temperature at the leading edge of the wing decreases by 304 K, and the minimum temperature of the tail increases by 130 K. The heat flow is dredged from the high-temperature zone to the low-temperature zone, and the thermal load of the leading edge of the wing is weakened. The same result can be obtained by the arc wind tunnel test, which verifies the accuracy of the numerical method and the feasibility of the dredging thermal protection structure with high-temperature heat pipe embedded in the leading edge of the wing.
Evolution of late Paleozoic shearing in the Cobequid Highlands: constraints on the fragmentation of the Appalachian Orogen in Nova Scotia along intra-continental shear zones
Authors: Piper David J. W. , Pe-Piper Georgia 
Published: April 2020

Abstract
The Cobequid Highlands of northern Nova Scotia lie at the intersection of two major dextral intra-continental shear zones which developed during closure of the Rheic Ocean and formation of Pangea. The Cobequid Shear Zone was an ENE–WSW transfer zone in a NE–SW-trending, orogen-parallel, shear system in the late Devonian–early Carboniferous (Neo-Acadian phase), in which syntectonic granite–gabbro plutons and volcanic strata <4 km thick were progressively deformed along multiple faults. In the Late Carboniferous–Permian, the Alleghanian collision of Africa with Laurentia formed the east–west-trending Minas Fault Zone, reactivating parts of the Cobequid Shear Zone. This deformation was mostly taken up on the master Cobequid–Chedabucto Fault. Deformation chronology is well constrained by the biostratigraphy of syntectonic sedimentary rocks, and by radiometrically dated igneous rocks and minerals in faults and veins. Early strike-slip faults were lubricated by magmatic heating, leading to dyke-to-pluton construction along multiple faults. During cooling, rooted gabbro was more resistant than ductile granite, thereby deflecting solid-state deformation. Neo-Acadian strike-slip displacement across the shear zone is estimated as >50 km. The location of Alleghanian deformation was influenced by the paucity of magmatism and the resistance offered by older stitching plutons.
Serum Concentrations of Emerging Vitamin D Biomarkers and Detection of Prevalent High-Risk HPV Infection in Mid-adult Women
Authors: Troja Catherine , Hoofnagle Andrew N. , Szpiro Adam , Stern Joshua E. , Lin John , Winer Rachel L. 
Published: April 2020

Abstract

Background:
Vitamin D has potential immunomodulating benefits in infection. One prior population-based cross-sectional study showed a protective association between serum concentrations of 25(OH)D and high-risk human papillomavirus (hrHPV) detection. Additional biomarkers present at different stages along the vitamin D metabolic pathway may more completely characterize vitamin D status but have not yet been evaluated in relation to hrHPV infection.

Methods:
Stored sera from women aged 30–50 years (N = 404) enrolled in an HPV natural history study from 2011–2012 were tested for 25(OH)D and 4 novel vitamin D biomarkers: 1,25(OH)2D, 24,24(OH)2D3, free vitamin D, and vitamin D–binding protein. Cross-sectional associations between vitamin D serum concentrations and cervicovaginal hrHPV detection were estimated using logistic regression.

Results:
25(OH)D serum concentrations were not associated with hrHPV. After adjusting for age, race, season, education, oral contraceptive use, smoking status, body mass index, and serum concentrations of calcium and phosphate, each 1 ng/mL increase in 24,25(OH)2D3 was nearly statistically significantly associated with higher likelihood of hrHPV detection [aOR = 1.22; 95% confidence interval (CI), 0.97–1.52]. No significant associations were observed for other biomarkers.

Conclusions:
25(OH)D serum concentrations were unassociated with prevalent hrHPV. Higher levels of one novel biomarker, 24,25(OH)2D3, were positively associated with hrHPV, an unexpected finding.

Impact:
Inconsistent with previous findings of a protective association between 25(OH)D and prevalent hrHPV infection, these results suggest serum concentrations of 4 vitamin D biomarkers are unassociated with detection of hrHPV in mid-adult women.
Improving AML Classification Using Splicing Signatures
Authors: Bowman Teresa V. 
Published: April 2020

Abstract
Mutations in spliceosomal components are prevalent in myelodysplastic syndromes, but less so in acute myeloid leukemia (AML). However, aberrant splicing is prolific in AML, suggesting deregulated splicing could contribute broadly to tumorigenesis. Elevated stress responses correlate with splicing dysfunction across myeloid malignancies, representing potentially novel therapeutic targets.
See related article by Anande et al., p. 3597
Physical Activity and Risk of Hepatocellular Carcinoma Among U.S. Men and Women
Authors: Luo Xiao , Yang Wanshui , Ma Yanan , Simon Tracey G. , Meyerhardt Jeffrey A. , Chan Andrew T. , Giovannucci Edward L. , Zhang Xuehong 
Published: April 2020

Abstract
Mounting evidence indicates a potential beneficial effect of vigorous-intensity physical activity on hepatocellular carcinoma (HCC). However, the association between moderate-intensity physical activity, such as brisk walking, and the risk of HCC remains largely unknown. Two prospective cohorts of 77,535 women from the Nurses' Health Study and 44,540 men from the Health Professionals Follow-up Study were included. Weekly time spent on physical activities were updated biennially. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HR) and 95% confidence intervals (95% CI). After an average 23-year follow-up, we identified 138 incident HCC cases. A higher amount of total physical activity was not significantly associated with a reduced risk of HCC (top tertile vs. bottom tertile; HR = 0.78; 95% CI, 0.51–1.18; Ptrend = 0.33). For the same comparison, there was an inverse association between moderate-intensity activity and HCC risk (HR = 0.60; 95% CI, 0.38–0.94; Ptrend = 0.04), whereas no statistically significant association with vigorous-intensity activity (HR = 0.88; 95% CI, 0.56–1.37; Ptrend = 0.74). Engaging in brisk walking was significantly associated with a lower risk of HCC (over 1 hour/week vs. non-brisk walking; HR = 0.50; 95% CI, 0.31–0.78; Ptrend = 0.006). The association between brisk walking and HCC risk was generally present across all subgroups, including age, body mass index, type 2 diabetes mellitus, smoking status, aspirin use, and alcohol consumption (all Pinteraction ≥ 0.05). In conclusion, moderate-intensity activity, especially brisk walking, was associated with reduced risk of HCC among U.S. men and women. If confirmed, brisk walking might serve a feasible way for HCC prevention.
Randomized Phase IIB Trial of the Lignan Secoisolariciresinol Diglucoside in Premenopausal Women at Increased Risk for Development of Breast Cancer
Authors: Fabian Carol J. , Khan Seema A. , Garber Judy E. , Dooley William C. , Yee Lisa D. , Klemp Jennifer R. , Nydegger Jennifer L. , Powers Kandy R. , Kreutzjans Amy L. , Zalles Carola M. , Metheny Trina , Phillips Teresa A. , Hu Jinxiang , Koestler Devin C. , Chalise Prabhakar , Yellapu Nanda Kumar , Jernigan Cheryl , Petroff Brian K. , Hursting Stephen D. , Kimler Bruce F. 
Published: April 2020

AbstractWe conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was −1.8% in the SDG arm (P = 0.001) and −1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = −2.2%; P = 0.002) but not placebo (median = −1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (&lt;0.5 or &gt;2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.
Novel Echocardiographic Approach to Hemodynamic Phenotypes Predicts Outcome of Patients Hospitalized With Heart Failure
Authors: Mele Donato , Pestelli Gabriele , Dini Frank Lloyd , Dal Molin Davide , Smarrazzo Vittorio , Trevisan Filippo , Luisi Giovanni Andrea , Ferrari Roberto 
Published: April 2020

Background:
Although in clinical practice heart failure (HF) patients are classified using left ventricular ejection fraction (LVEF), this categorization is insufficient for prognosis, especially when LVEF is preserved or there is a concomitant right ventricular (RV) dysfunction. We hypothesized that a combined noninvasive evaluation of LV forward flow, filling pressure, and RV function would be better than LVEF in predicting all-cause mortality of hospitalized patients with HF.

Methods:
Transthoracic echocardiographic examinations of 603 patients hospitalized with HF were analyzed. In a subsample of 200 patients with HF, LV stroke volume index, LV filling pressure estimation, tricuspid annular plane systolic excursion, and systolic pulmonary artery pressure were combined to determine 4 hemodynamic profiles: normal flow-normal pressure, normal flow-high pressure, low flow without RV dysfunction, and low flow with RV dysfunction profile. This model was then applied in a validation cohort (n=403).

Results:

Prognosis worsened from the normal flow-normal pressure profile to the low flow with right ventricular dysfunction profile. At the multivariate survival analysis, the model showed independent high risk-stratification capability (
P
<0.001), even in subgroups of patients with LVEF < or ≥50% (
P
=0.011 and
P
<0.001, respectively) and < or ≥40% (
P
=0.044 and
P
<0.001, respectively). LVEF and HF classification based on LVEF did not predict outcome.

Conclusions:
Echocardiographic-derived profiling of LV forward flow, filling pressure, and RV function allowed categorization of patients hospitalized with HF and predicted all-cause mortality independently of LVEF. This model is based on conventional echocardiography, is easy to apply, and is, therefore, suggested for clinical practice.
Mesenchymal Stromal Cell–Derived Small Extracellular Vesicles Induce Ischemic Neuroprotection by Modulating Leukocytes and Specifically Neutrophils
Authors: Wang Chen , Börger Verena , Sardari Maryam , Murke Florian , Skuljec Jelena , Pul Refik , Hagemann Nina , Dzyubenko Egor , Dittrich Robin , Gregorius Jonas , Hasenberg Mike , Kleinschnitz Christoph , Popa-Wagner Aurel , Doeppner Thorsten R. , Gunzer Matthias , Giebel Bernd , Hermann Dirk M. 
Published: April 2020

Background and Purpose—
Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) were shown to induce neurological recovery after focal cerebral ischemia in rodents and to reverse postischemic lymphopenia in peripheral blood. Since peripheral blood cells, especially polymorphonuclear neutrophils (PMNs), contribute to ischemic brain injury, we analyzed brain leukocyte responses to sEVs and investigated the role of PMNs in sEV-induced neuroprotection.

Methods—
Male C57Bl6/j mice were exposed to transient intraluminal middle cerebral artery occlusion. After reperfusion, vehicle or sEVs prepared from conditioned media of MSCs raised from bone marrow samples of 3 randomly selected healthy human donors were intravenously administered. sEVs obtained from normoxic and hypoxic MSCs were applied. PMNs were depleted in vehicle and MSC-sEV–treated mice. Neurological deficits, ischemic injury, blood-brain barrier integrity, peripheral blood leukocyte responses, and brain leukocyte infiltration were evaluated over 72 hours.

Results—

sEV preparations of all 3 donors collected from normoxic MSCs significantly reduced neurological deficits. Preparations of 2 of these donors significantly decreased infarct volume and neuronal injury. sEV-induced neuroprotection was consistently associated with a decreased brain infiltration of leukocytes, namely of PMNs, monocytes/macrophages, and lymphocytes. sEVs obtained from hypoxic MSCs (1% O
2
) had similar effects on neurological deficits and ischemic injury as MSC-sEVs obtained under regular conditions (21% O
2
) but also reduced serum IgG extravasation—a marker of blood-brain barrier permeability. PMN depletion mimicked the effects of MSC-sEVs on neurological recovery, ischemic injury, and brain PMN, monocyte, and lymphocyte counts. Combined MSC-sEV administration and PMN depletion did not have any effects superior to PMN depletion in any of the readouts examined.

Conclusions—
Leukocytes and specifically PMNs contribute to MSC-sEV–induced ischemic neuroprotection. Individual MSC-sEV preparations may differ in their neuroprotective activities. Potency assays are urgently needed to identify their therapeutic efficacy before clinical application.

Visual Overview—

An online
visual overview
is available for this article.
Hemi-laryngopharyngeal Spasm (HeLPS): Defining a New Clinical Entity
Authors: Hu Amanda , Morrison Murray , Honey Christopher R. 
Published: April 2020

Objective: Hemi-laryngopharyngeal spasm (HeLPS) has recently been described in the neurosurgical literature as a cause of intermittent laryngopharyngeal spasm and cough due to vascular compression of the vagus nerve at the cerebellopontine angle. We present the diagnostic criteria for this syndrome. Methods: A retrospective chart review of six patients with HeLPS and three patients misdiagnosed with this condition are presented. All patients were diagnosed and treated at a tertiary care academic centre from July 2013 to July 2017. Results: Patients with HeLPS had five defining characteristics: 1) All patients had symptoms of episodic laryngopharyngeal spasm and coughing. Patients were asymptomatic between episodes and were refractory to speech therapy and reflux management. 2) Laryngoscopy showed hyperactive twitching of the ipsilateral vocal fold in two of the six patients. No other inter-episodic abnormalities were seen. 3) Botulinum toxin A injections into the thyroarytenoid muscle on the affected ipsilateral side reduced laryngopharyngeal spasms. Botulinum toxin injection in the contralateral thyroarytenoid muscle did not improve laryngopharyngeal spasm. 4) Magnetic resonance imaging revealed ipsilateral neurovascular compression of the vagus nerve rootlets by the posterior inferior cerebellar artery. 5) Microvascular decompression (MVD) surgery of the ipsilateral vagus nerve resolved all symptoms (follow-up 2-4 years). Conclusion: The diagnostic criteria for hemi-laryngopharyngeal spasm (HeLPS) are proposed. Otolaryngology recognition of this new clinical entity may lead to a surgical cure and avoid the unnecessary therapies associated with misdiagnosis. Level of Evidence: 4