bluuebunny/crossref_metadata_2025 huggingface dataset:
Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
Authors: Liu Chen , Lu Hengyu , Wang Hongyun , Loo Alice , Zhang Xiamei , Yang Guizhi , Kowal Colleen , Delach Scott , Wang Ye , Goldoni Silvia , Hastings William D. , Wong Karrie , Gao Hui , Meyer Matthew J. , Moody Susan E. , LaMarche Matthew J. , Engelman Jeffrey A. , Williams Juliet A. , Hammerman Peter S. , Abrams Tinya J. , Mohseni Morvarid , Caponigro Giordano , Hao Huai-Xiang
Published: October 2020

Purpose:

SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development.

Experimental Design:

The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined.

Results:

In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody.

Conclusions:

Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.
Activity and Safety of Geptanolimab (GB226) for Patients with Unresectable, Recurrent, or Metastatic Alveolar Soft Part Sarcoma: A Phase II, Single-arm Study
Authors: Shi Yuankai , Cai Qiqing , Jiang Yu , Huang Gang , Bi Minghong , Wang Baocheng , Zhou Yuhong , Wang Guowen , Ying Hongyan , Tao Zhiwei , Shi Chunmei , Guo Qian , Gao Chao
Published: October 2020

Purpose:

Patients with alveolar soft part sarcoma (ASPS) are rare and have few treatment options. We assessed the activity of geptanolimab (GB226), a fully humanized programmed cell death protein 1 antibody, for patients with unresectable, recurrent, or metastatic ASPS.

Patients and Methods:

We conducted this multicenter, single-arm, phase II study (Gxplore-005, NCT03623581) in patients aged 18–75 years who had unresectable, recurrent, or metastatic ASPS at 11 sites in China. Patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by independent review committee (IRC) per RECIST 1.1 in the full analysis set population.

Results:

Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. Fourteen [37.8%; 95% confidence interval (CI), 22.5–55.2] of 37 patients had an objective response assessed by IRC with a 6-month duration of response rate of 91.7%. Median progression-free survival was 6.9 months (95% CI, 5.0–not reached) and disease control was achieved in 32 (86.5%; 95% CI, 71.2–95.5) patients. Three of 37 patients reported grade 3 treatment-related adverse events (TRAEs), including anemia, hypophysitis, and proteinuria [one each (2.7%)]. No grade 4 TRAEs were observed. Two (5.4%) patients discontinued treatment due to TRAEs (one with hypophysitis and one with Mobitz type I atrioventricular block). The baseline percentage of CD4+ T cells was adversely associated with patient response (P = 0.031).

Conclusions:

Geptanolimab has clinically meaningful activity and a manageable safety profile in unresectable, recurrent, or metastatic ASPS.
Dephosphorylation of the Proneural Transcription Factor ASCL1 Re-Engages a Latent Post-Mitotic Differentiation Program in Neuroblastoma
Authors: Ali Fahad R. , Marcos Daniel , Chernukhin Igor , Woods Laura M. , Parkinson Lydia M. , Wylie Luke A. , Papkovskaia Tatiana D. , Davies John D. , Carroll Jason S. , Philpott Anna
Published: October 2020

Pediatric cancers often resemble trapped developmental intermediate states that fail to engage the normal differentiation program, typified by high-risk neuroblastoma arising from the developing sympathetic nervous system. Neuroblastoma cells resemble arrested neuroblasts trapped by a stable but aberrant epigenetic program controlled by sustained expression of a core transcriptional circuit of developmental regulators in conjunction with elevated MYCN or MYC (MYC). The transcription factor ASCL1 is a key master regulator in neuroblastoma and has oncogenic and tumor-suppressive activities in several other tumor types. Using functional mutational approaches, we find that preventing CDK-dependent phosphorylation of ASCL1 in neuroblastoma cells drives coordinated suppression of the MYC-driven core circuit supporting neuroblast identity and proliferation, while simultaneously activating an enduring gene program driving mitotic exit and neuronal differentiation.

Implications:

These findings indicate that targeting phosphorylation of ASCL1 may offer a new approach to development of differentiation therapies in neuroblastoma.
A TLR3 Ligand Reestablishes Chemotherapeutic Responses in the Context of FPR1 Deficiency
Authors: Le Naour Julie , Liu Peng , Zhao Liwei , Adjemian Sandy , Sztupinszki Zsofia , Taieb Julien , Mulot Claire , Silvin Aymeric , Dutertre Charles-Antoine , Ginhoux Florent , Sauvat Allan , Cerrato Giulia , Castoldi Francesca , Martins Isabelle , Stoll Gautier , Paillet Juliette , Mangane Khady , Richter Cornelia , Kepp Oliver , Maiuri Maria Chiara , Pietrocola Federico , Vandenabeele Peter , André Fabrice , Delaloge Suzette , Szallasi Zoltan , Laurent-Puig Pierre , Zucman-Rossi Jessica , Zitvogel Laurence , Pol Jonathan G. , Vacchelli Erika , Kroemer Guido
Published: October 2020

For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Here, we show that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy of tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC- and T-lymphocyte–mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.

Significance:

The loss-of-function variant rs867228 in FPR1, harbored by approximately 30% of the world population, is associated with the precocious manifestation of breast, colorectal, esophageal, and head and neck carcinomas. pIC restores deficient chemotherapeutic responses in mice lacking Fpr1, suggesting a personalized strategy for compensating for the FPR1 defect.

This article is highlighted in the In This Issue feature, p. 211
Rituximab, Cyclophosphamide, and Corticosteroids for ANCA Vasculitis: The Good, the Bad, and the Ugly
Authors: Fenoglio Roberta , Roccatello Dario , Sciascia Savino
Published: October 2020

Backgrounds: ANCA-associated vasculitis (AAV) frequently present with a chronic relapsing course. Relapse leads to an increased need for therapeutic agents and consequent toxicity. Summary: When referring to the available options for the management of AAV, the efficacy of glucocorticoids (GCs) is unquestionable. However, similarly unquestionable are their side effects. It has been more than 40 years since the efficacy of cyclophosphamide (CYC) as an add-on therapy to GCs in the management of necrotizing vasculitis has been proven. At the same time, concerns about the devastating side effects related to a prolonged exposure to this agent were raised. Despite the well-known side effects, the management of AAV remained centred on CYC until the early 2000s, when the pilot data first supporting the anecdotal efficacy of rituximab (RTX) were reported. However, it was not until 2010 that the non-inferiority of RTX to CYC for remission-induction in AAVs was demonstrated in 2 randomized controlled trials. Key Messages: Treatment of AAV has improved over the last decade, and currently available strategies are able to induce remission in the majority of the cases. Herewith, we aim to critically review available evidence and to critically address the following question: How can we reduce the GCs use the management of patients with AAV? Novel strategies that avoid the toxicity associated with currently used agents should be the goal. Ideally, these approaches should be GC-free.
PolyADP-Ribosylation of NFATc3 and NF-κB Transcription Factors Modulate Macrophage Inflammatory Gene Expression in LPS-Induced Acute Lung Injury
Authors: Nie Yunjuan , Nirujogi Teja Srinivas , Ranjan Ravi , Reader Brenda F. , Chung Sangwoon , Ballinger Megan N. , Englert Joshua A. , Christman John W. , Karpurapu Manjula
Published: October 2020

Pulmonary macrophages play a critical role in the recognition of pathogens, initiation of host defense via inflammation, clearance of pathogens from the airways, and resolution of inflammation. Recently, we have shown a pivotal role for the nuclear factor of activated T-cell cytoplasmic member 3 (NFATc3) transcription factor in modulating pulmonary macrophage function in LPS-induced acute lung injury (ALI) pathogenesis. Although the NFATc proteins are activated primarily by calcineurin-dependent dephosphorylation, here we show that LPS induces posttranslational modification of NFATc3 by polyADP-ribose polymerase 1 (PARP-1)-mediated polyADP-ribosylation. ADP-ribosylated NFATc3 showed increased binding to iNOS and TNFα promoter DNA, thereby increasing downstream gene expression. Inhibitors of PARP-1 decreased LPS-induced NFATc3 ribosylation, target gene promoter binding, and gene expression. LPS increased NFAT luciferase reporter activity in lung macrophages and lung tissue that was inhibited by pretreatment with PARP-1 inhibitors. More importantly, pretreatment of mice with the PARP-1 inhibitor olaparib markedly decreased LPS-induced cytokines, protein extravasation in bronchoalveolar fluid, lung wet-to-dry ratios, and myeloperoxidase activity. Furthermore, PARP-1 inhibitors decreased NF-кB luciferase reporter activity and LPS-induced ALI in NF-кB reporter mice. Thus, our study demonstrates that inhibiting NFATc3 and NF-кB polyADP-ribosylation with PARP-1 inhibitors prevented LPS-induced ALI pathogenesis.
Nephrometry Scores: Can Preoperative Assessment of Sectional Imaging Really Mirror Intraoperative Renal Tumor Anatomy?
Authors: Egen Luisa , Kowalewski Karl-Friedrich , Riffel Philipp , Honeck Patrick , Kriegmair Maximilian C.
Published: October 2020

Introduction: To compare RENAL, preoperative aspects and dimensions used for an anatomical (PADUA) classification, and Mayo Adhesive Probability (MAP) scores with the respective intraoperative findings and surgeon’s assessment in predicting surgical outcome of patients undergoing partial nephrectomy. Methods: Data of 150 eligible patients treated at the University Medical Center Mannheim between 2016 and 2018 were analyzed. Tumors were radiologically and intraoperatively assessed by PADUA, RENAL, and MAP scores and surgeon’s assessment. Correlations and regression models were created to predict ischemia time (IT), major complications, and Trifecta (negative surgical margin, IT < 25 min, and absence of major complications). Results: There were strong correlations between radiological and intraoperative RENAL (r = 0.68; p < 0.001) and PADUA scores (r = 0.72; p < 0.001). Radiological RENAL, PADUA, and MAP scores and surgeon’s assessment were independent predictors of Trifecta (OR = 0.71, p = 0.015; OR = 0.77, p = 0.035; OR = 0.65, p = 0.012; OR = 0.40, p = 0.005, respectively). IT showed significant associations with radiological RENAL, PADUA, and surgeon’s assessment (OR = 1.41, p = 0.033; OR = 1.34, p = 0.044; OR = 3.04, p = 0.003, respectively). MAP score proved as only independent predictor of major complications (OR = 2.12, p = 0.002). Conclusion: Radiologically and intraoperatively assessed scores correlated well with each other. Intraoperative nephrometry did not outperform radiological scores in predicting outcome confirming the value of the existing systems. MAP score correlates well with surgeon’s assessment of perirenal fat and major complications underlining the importance of perirenal fat characteristics.
Artificial Intelligence in Medicine: Chances and Challenges for Wide Clinical Adoption
Authors: Varghese Julian
Published: October 2020

Background: Artificial intelligence (AI) applications that utilize machine learning are on the rise in clinical research and provide highly promising applications in specific use cases. However, wide clinical adoption remains far off. This review reflects on common barriers and current solution approaches. Summary: Key challenges are abbreviated as the RISE criteria: Regulatory aspects, Interpretability, interoperability, and the need for Structured data and Evidence. As reoccurring barriers of AI adoption, these concepts are delineated and complemented by points to consider and possible solutions for effective and safe use of AI applications. Key Messages: There is a fraction of AI applications with proven clinical benefits and regulatory approval. Many new promising systems are the subject of current research but share common issues for wide clinical adoption. The RISE criteria can support preparation for challenges and pitfalls when designing or introducing AI applications into clinical practice.
Coronary Artery Bypass Grafting or Fractional Flow Reserve–Guided Percutaneous Coronary Intervention in Diabetic Patients With Multivessel Disease
Authors: Di Gioia Giuseppe , Soto Flores Nina , Franco Danilo , Colaiori Iginio , Sonck Jeroen , Gigante Carlo , Kodeboina Monika , Bartunek Jozef , Vanderheyden Marc , Van Praet Frank , Casselman Filip , Degriek Ivan , Stockman Bernard , Barbato Emanuele , Collet Carlos , De Bruyne Bernard
Published: October 2020

Background:

In diabetic patients with multivessel coronary artery disease, coronary artery bypass grafting (CABG) has shown long-term benefits over percutaneous coronary intervention (PCI). Physiology-guided PCI has shown to improve clinical outcomes in multivessel coronary artery disease, though its impact in diabetic patients has never been investigated. We evaluated long-term clinical outcomes of diabetic patients with multivessel coronary artery disease treated with fractional flow reserve (FFR)–guided PCI compared with CABG.

Methods:

From 2010 to 2018, 4622 diabetic patients undergoing coronary angiography were screened for inclusion. The inclusion criterion was the presence of at least 2-vessel disease defined as with diameter stenosis ≥50%, in which at least 1 intermediate stenosis (diameter stenosis, 30%–70%) was treated or deferred according to FFR. Inverse probability of treatment weighting analysis was used to account for baseline differences with a contemporary cohort of patients treated with CABG. The primary end point was major adverse cardiovascular and cerebrovascular events, defined as all-cause death, myocardial infarction, revascularization, or stroke.

Results:

A total of 418 patients were included in the analysis. Among them, 209 patients underwent CABG and 209 FFR-guided PCI. At 5 years, the incidence of major adverse cardiovascular and cerebrovascular events was higher in the FFR-guided PCI versus the CABG group (44.5% versus 31.9%; hazard ratio, 1.60 [95% CI, 1.15–2.22];
P
=0.005). No difference was found in the composite of all-cause death, myocardial infarction, or stroke (28.8% versus 27.5%; hazard ratio, 1.05 [95% CI, 0.72–1.53];
P
=0.81). Repeat revascularization was more frequent with FFR-guided PCI (24.9% versus 8.2%; hazard ratio, 3.51 [95% CI, 1.93–6.40];
P
<0.001).

Conclusions:

In diabetic patients with multivessel coronary artery disease, CABG was associated with a lower rate of major adverse cardiovascular and cerebrovascular events compared with FFR-guided PCI, driven by a higher rate of repeat revascularization. At 5-year follow-up, no difference was observed in the composite of all-cause death, myocardial infarction, or stroke between CABG and FFR-guided PCI.

Graphic Abstract:

A
graphic abstract
is available for this article.
Association of Disease Progression With Cardiovascular and Limb Outcomes in Patients With Peripheral Artery Disease
Authors: Rymer Jennifer A. , Mulder Hillary , Narcisse Dennis I. , Rockhold Frank , Hiatt William R. , Fowkes F. Gerry , Baumgartner Iris , Berger Jeffrey S. , Katona Brian G. , Mahaffey Kenneth , Norgren Lars , Blomster Juuso I. , Jones W. Schuyler , Patel Manesh R.
Published: October 2020

Background:

Patients with peripheral artery disease have a high risk of future cardiovascular disease events and mortality. Little is known about the changes in symptom classification over time in patients with peripheral artery disease and the association of changes in symptom classification with subsequent cardiovascular disease events.

Methods:

In this analysis of the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease), we examined the changes in Rutherford classification (RC) of patients over 12 months. We examined the baseline characteristics of patients by change in symptom classification at 12 months (improved=decreased RC, no change, or worsened=increased RC), and the association between changes in symptom classification (RC) at 12 months and subsequent cardiovascular disease events.

Results:

Among 12 759 patients, 3240 (25%) were classified as improved by RC at 12 months, 8132 (64%) as no change, and 1387 (11%) as worsened. At 12 months, many patients who were asymptomatic or had mild/moderate claudication at enrollment had no change in symptom classification over 12 months (73.7% and 70.9%). Patients who worsened over 12 months were more likely to have comorbidities (diabetes mellitus and prior myocardial infarction) and more events (myocardial infarction, amputation, and major bleeding) by 12 months postrandomization, all
P
<0.001. Worsened symptom classification over 12 months was associated with increased risk of all-cause death (adjusted hazard ratio, 1.29 [95% CI, 1.03–1.62]), major amputation (adjusted hazard ratio, 4.12 [95% CI, 2.46–6.88]), and a composite of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 1.30 [95% CI, 1.05–1.62]), all
P
<0.05 after 12 months postrandomization.

Conclusions:

Patients with comorbidities and prior history of cardiovascular disease events at baseline and within the first 12 months of the trial were more likely to have worsened symptom classification at 12 months. Worsening symptom classification over 12 months was associated subsequently with an increased risk of all-cause death, amputation, and a composite of cardiovascular death, myocardial infarction, or stroke.

Graphic Abstract:

A
graphic abstract
is available for this article.
Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Jhund Pardeep S. , Solomon Scott D. , Docherty Kieran F. , Heerspink Hiddo J.L. , Anand Inder S. , Böhm Michael , Chopra Vijay , de Boer Rudolf A. , Desai Akshay S. , Ge Junbo , Kitakaze Masafumi , Merkley Bela , O'Meara Eileen , Shou Morten , Tereshchenko Sergey , Verma Subodh , Vinh Pham Nguyen , Inzucchi Silvio E. , Køber Lars , Kosiborod Mikhail N. , Martinez Felipe A. , Ponikowski Piotr , Sabatine Marc S. , Bengtsson Olof , Langkilde Anna Maria , Sjöstrand Mikaela , McMurray John J.V.
Published: October 2020

Background:

Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease that complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure). We also examined the effect of dapagliflozin on kidney function after randomization.

Methods:

Patients who have HFrEF with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL·min
–1
·1.73 m
–2
were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) according to eGFR category at baseline (<60 and ≥60 mL·min
–1
·1.73 m
–2
) and used eGFR at baseline as a continuous measure, as well. Secondary cardiovascular outcomes and a prespecified composite renal outcome (≥50% sustained decline eGFR, end-stage renal disease, or renal death) were also examined, along with a decline in eGFR over time.

Results:

Of 4742 patients with a baseline eGFR, 1926 (41%) had eGFR <60 mL·min
–1
·1.73 m
–2
. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% CI) for the primary end point in patients with chronic kidney disease was 0.71 (0.59–0.86) versus 0.77 (0.64–0.93) in those with an eGFR ≥60 mL·min
–1
·1.73 m
–2
(interaction
P
=0.54). The composite renal outcome was not reduced by dapagliflozin (hazard ratio=0.71 [95% CI, 0.44–1.16];
P
=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, –1.09 (–1.40 to –0.77) versus placebo –2.85 (–3.17 to –2.53) mL·min
–1
·1.73 m
–2
per year (
P
<0.001). This was observed in those with and without type 2 diabetes (
P
for interaction=0.92).

Conclusions:

Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF, and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03036124.
Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source
Authors: Grosse Gerrit M. , Sieweke Jan-Thorben , Biber Saskia , Ziegler Nora L. , Gabriel Maria M. , Schuppner Ramona , Worthmann Hans , Bavendiek Udo , Weissenborn Karin
Published: October 2020

Background and Purpose:

Approximately one-sixth of all ischemic strokes are attributable to embolic stroke of undetermined source (ESUS). Recent analyses suggest that atrial cardiopathy and nonstenotic carotid plaque (nsCP) may represent 2 distinct underlying causes in patients with ESUS, although both diseases share common risk factors and are pathophysiologically intertwined. In this study, we, therefore, aimed to search for associations between nsCP and markers of atrial remodeling and function in patients with embolic stroke.

Methods:

Sixty-eight patients with ESUS or atrial fibrillation (AF)-related stroke proven by imaging who underwent comprehensive echocardiographic studies, including measurements of left atrial function and remodeling, were considered. Patients with ESUS underwent a follow-up of at least 1 year after index stroke. For 20 patients with ESUS, NT-proBNP (N-terminal pro-B-type natriuretic peptide) values were available. Presence of nsCP was evaluated considering Duplex sonography and computed tomography angiography and was further categorized in possibly or probably symptomatic nsCP.

Results:

ESUS patients with nsCP tended to have higher values of septal and lateral total atrial conduction times (
P
=0.071 and
P
=0.072, respectively), left atrial volume index (
P
=0.077), and revealed significantly higher strain rates during early diastole (
P
=0.013) as well as higher NT-proBNP values (
P
=0.010) than ESUS patients without nsCP. Moreover, septal total atrial conduction time was significantly longer in ESUS patients with possibly symptomatic nsCP compared with those without (
P
=0.015). Comparison of ESUS with AF patients revealed significantly higher proportions of nsCP (
P
=0.010), possibly symptomatic nsCP (
P
=0.037), and probably symptomatic nsCP (
P
=0.036) in patients with atrial fibrillation-related stroke. In the regression analysis adjusted for vascular risk factors probably symptomatic nsCP remained significantly associated with AF (
P
=0.048, odds ratio: 4.46 [95% CI, 1.02–19.56]).

Conclusions:

Presence of nsCP is associated with AF and markers of left atrial disease in patients with embolic stroke. Therefore, a thorough evaluation regarding atrial cardiopathy and AF in patients with ESUS should not be restricted if nsCP are found, even if high-risk plaque characteristics are evident.
Internet Video Calling and Desktop Sharing (vcds) as an Emerging Research Method for Exploring Pedagogical Reasoning in Lesson Planning
Authors: Hidson Elizabeth
Published: October 2020

This article presents the specific case of video calling and desktop sharing (vcds) used in a small-scale doctoral study exploring the lesson planning processes of teachers as a result of a national curriculum change. Accessing the participants’ actions and live think-aloud exposition of their pedagogical practices also generated dialogue as new data. The study set out to explore how pedagogical content knowledge was enacted through pedagogical reasoning when participant teachers planned Computing lessons. Two central case studies captured using vcds are shared. One presents a dialogic research interview which developed a shared understanding of the impact of the curriculum change on one teacher’s practices. The second case study shows the potential of vcds to capture the verbalised thoughts and observable actions of a second teacher preparing to teach new programming skills. The video data collected provided a rich audio-visual record of the lesson planning process as it happened. This article shares the approach taken, exemplifies the data captured and reflects on vcds as a method for exploring teachers’ pedagogical reasoning. It concludes that, depending on the nature of the research question, vcds may be justified as more suitable than face-to-face, artefact-based interviews.
A new species of Eunice Cuvier, 1817 (Polychaeta: Eunicidae) from the slope of the Desventuradas Islands and seamounts of the Nazca Ridge, southeastern Pacific Ocean
Authors: DÍAZ-DÍAZ OSCAR FELIPE , ROZBACZYLO NICOLÁS , SELLANES JAVIER , TAPIA-GUERRA JAN M.
Published: October 2020

A new species of Eunicidae, Eunice decolorhami sp. n., from the southeastern Pacific Ocean, is described. The species was collected at the slope of the Desventuradas Islands (San Félix and San Ambrosio) and in three nearby seamounts of the Nazca Ridge, in dead coral rubble bottoms from 180 to 340 m depth and inhabiting inside parchment-like branched tubes. Eunice decolorhami sp. n. can be distinguished from other species of the genus, mainly by the coloration pattern of the subacicular hooded hooks along the body segments, the beginning of the subacicular hooded hooks, the beginning of the branchiae, the maximum number of branchial filaments, and the maxillary formula. A key for the seven Eunice species recorded off the coast of Chile and Peru, including the new species described herein, is provided.
Vertical Variability of the Raindrop Size Distribution in Typhoons Observed at the Shenzhen 356-m Meteorological Tower
Authors: Chen Baojun , Yang Jun , Gao Ruiquan , Zhu Keping , Zou Chungen , Gong Yi , Zhang Ran
Published: October 2020

Raindrop size distribution (DSD) characteristics at various altitudes in two landfalling typhoons in 2017 (Hato and Pakhar) were investigated by using laser-optical disdrometers mounted at four altitudes (10, 40, 160, and 320 m) of the Shenzhen 356-m meteorological tower. Significant differences of the DSD and derived parameters, mass-weighted mean diameter (Dm), normalized intercept parameter (NW), and standard deviation of the mass distribution σm, were observed at different altitudes for the two typhoons, while the rainwater content between the four altitudes had no statistically significant differences. The low-altitude DSDs had more midsize drops (1 < D < 3 mm), fewer large drops (D > 3 mm), and narrower distribution widths than the high-altitude ones, while the concentration of small drops varied nonlinearly with height. The value of NW decreased with height, while Dm and σm increased with height. The gamma distribution parameters N0, μ, and Λ are found to increase with decreasing height. Both the derived μ–Λ and Z–R relations were significantly varied in different altitudes.
Cold Surge Pathways in East Asia and Their Tropical Impacts
Authors: Abdillah Muhammad Rais , Kanno Yuki , Iwasaki Toshiki , Matsumoto Jun
Published: October 2020

Cold surge occurrences are one of the robust features of winter monsoon in East Asia and are characterized by equatorward outbreaks of cold air from the high latitudes. Beside greatly affecting weather variability across the Far East, cold surges are of importance for Southeast Asian countries because they can propagate far to the tropics and excite convective activities. However, the tropical responses highly depend on the downstream pathways of the surges. To better understand how cold surges influence tropical weather, we investigate 160 cold surges identified using a quantitative approach during 40 winters from 1979/80 to 2018/19, and then classify them into several groups based on their prominent pathways. At the midlatitudes, we find two groups: one for surges that show clear equatorward propagation of cold air to lower latitudes and the other for surges that turn eastward and bring cold air to the North Pacific. These groups arise due to the strength difference of the Siberian high expansion controlled by cold air blocking near the Tibetan Plateau. The tropical impact is evident in the former group. We perform further classification on this group and find four types of surges based on their pathways in the low latitudes: 1) South China Sea (SCS) surges, 2) Philippines Sea (PHS) surges, 3) both SCS and PHS surges, and 4) blocked surges. They exhibit distinct precipitation signatures over the Maritime Continent, which are driven by interactions between the surges and the pre-existing synoptic conditions over the tropics, particularly the Madden–Julian oscillation (MJO).
PERSIANN Dynamic Infrared–Rain Rate (PDIR-Now): A Near-Real-Time, Quasi-Global Satellite Precipitation Dataset
Authors: Nguyen Phu , Ombadi Mohammed , Gorooh Vesta Afzali , Shearer Eric J. , Sadeghi Mojtaba , Sorooshian Soroosh , Hsu Kuolin , Bolvin David , Ralph Martin F.
Published: October 2020

This study presents the Precipitation Estimation from Remotely Sensed Information Using Artificial Neural Networks–Dynamic Infrared Rain Rate (PDIR-Now) near-real-time precipitation dataset. This dataset provides hourly, quasi-global, infrared-based precipitation estimates at 0.04° × 0.04° spatial resolution with a short latency (15–60 min). It is intended to supersede the PERSIANN–Cloud Classification System (PERSIANN-CCS) dataset previously produced as the near-real-time product of the PERSIANN family. We first provide a brief description of the algorithm’s fundamentals and the input data used for deriving precipitation estimates. Second, we provide an extensive evaluation of the PDIR-Now dataset over annual, monthly, daily, and subdaily scales. Last, the article presents information on the dissemination of the dataset through the Center for Hydrometeorology and Remote Sensing (CHRS) web-based interfaces. The evaluation, conducted over the period 2017–18, demonstrates the utility of PDIR-Now and its improvement over PERSIANN-CCS at all temporal scales. Specifically, PDIR-Now improves the estimation of rain/no-rain days as demonstrated by a critical success index (CSI) of 0.53 compared to 0.47 of PERSIANN-CCS. In addition, PDIR-Now improves the estimation of seasonal and diurnal cycles of precipitation as well as regional precipitation patterns erroneously estimated by PERSIANN-CCS. Finally, an evaluation is carried out to examine the performance of PDIR-Now in capturing two extreme events, Hurricane Harvey and a cluster of summer thunderstorms that occurred over the Netherlands, where it is shown that PDIR-Now adequately represents spatial precipitation patterns as well as subdaily precipitation rates with a correlation coefficient (CORR) of 0.64 for Hurricane Harvey and 0.76 for the Netherlands thunderstorms.
Toward the Improvement of High-Impact Probabilistic Forecasts with a Sensitivity-Based Convective-Scale Ensemble Subsetting Technique
Authors: Coleman Austin , Ancell Brian
Published: October 2020

Ensemble sensitivity analysis (ESA) is a useful and computationally inexpensive tool for analyzing how features in the flow at early forecast times affect different relevant forecast features later in the forecast. Given the frequency of observations measured between model initialization times that remain unused, ensemble sensitivity may be used to increase predictability and forecast accuracy through an objective ensemble subsetting technique. This technique identifies ensemble members with the smallest errors in regions of high sensitivity to produce a smaller, more accurate ensemble subset. Ensemble subsets can significantly reduce synoptic-scale forecast errors, but applying this strategy to convective-scale forecasts presents additional challenges. Objective verification of the sensitivity-based ensemble subsetting technique is conducted for ensemble forecasts of 2–5-km updraft helicity (UH) and simulated reflectivity. Many degrees of freedom are varied to identify the lead times, subset sizes, forecast thresholds, and atmospheric predictors that provide most forecast benefit. Subsets vastly reduce error of UH forecasts in an idealized framework but tend to degrade fractions skill scores and reliability in a real-world framework. Results reveal this discrepancy is a result of verifying probabilistic UH forecasts with storm-report-based observations, which effectively dampens technique performance. The potential of ensemble subsetting and likely other postprocessing techniques is limited by tuning UH forecasts to predict severe reports. Additional diagnostic ideas to improve postprocessing tool optimization for convection-allowing models are discussed.
Reflective testing – A randomized controlled trial in primary care patients
Authors: Oosterhuis Wytze P , Venne Wilhelmine PHG Verboeket-van de , Deursen Cees TBM van , Stoffers Henri EJH , Acker Bernadette AC van , Bossuyt Patrick MM
Published: October 2020

Background

Reflective testing, i.e. interpreting, commenting on and, if necessary, adding tests in order to aid the diagnostic process in a meaningful and efficient manner, is an extra service provided by laboratory medicine. However, there have been no prospective randomized controlled trials investigating the value of reflective testing in patient management.

Methods

In this trial, primary care patients were randomly allocated to an intervention group, where general practitioners received laboratory tests results as requested as well as add-on test results with interpretative comments where considered appropriate by the laboratory specialist, or to a control group, where general practitioners only received the laboratory test results requested. Patients’ medical records were evaluated with a follow-up period of six months. For both groups, the primary outcome measures, i.e. both intended action and actual management action, were blindly assessed by an independent expert panel as adequate, neutral or inadequate.

Results

In 226 of the 270 cases (84%), reflective testing was considered to be useful for the patient. In the intervention group ( n = 148), actual management by the general practitioner was scored as adequate ( n = 104; 70%), neutral ( n = 29; 20%) or not adequate ( n = 15; 10%). In the control group ( n = 122), these numbers were 57 (47%), 37 (30%) and 28 (23%). This difference was statistically significant ( P < 0.001).

Conclusion

This randomized controlled trial showed a positive effect of reflective testing in primary care patients on the adequacy of their management, as documented in medical records.
Lp(a): When and how to measure it
Authors: Cegla Jaimini , France Michael , Marcovina Santica M , Neely R Dermot G
Published: October 2020

Lipoprotein(a) has long been regarded as a risk factor for cardiovascular disease; however, its routine use in clinical practice has been hampered by difficulties inherent in the measurement of this complex lipoprotein. The major challenges relate to its size heterogeneity and related issues including (1) use of appropriate calibrators (2) standardization of calibration protocols (3) traceability and (4) reporting units. In the UK, results from the current EQA schemes for lipoprotein(a) suggest that there is considerable work required to standardize lipoprotein(a) measurement. This is becoming increasingly pertinent with the increasing recognition of lipoprotein(a) as an independent risk factor for cardiovascular disease in international guidelines and the emergence of novel antisense therapies to effectively reduce lipoprotein(a). This article raises awareness of the importance of measurement of lipoprotein(a) for the assessment of cardiovascular disease risk and gives guidance to clinical laboratories regarding choice of appropriate assays.
Inappropriate Adults? A Review of the Current Use of Appropriate Adults in the Criminal Justice System
Authors: Dent Nick , O’Beirne Sean
Published: October 2020

Appropriate Adults (AAs) are an important procedural safeguard for young and vulnerable people in a criminal investigation. The significance of their role is recognised by Parliament in the Police and Criminal Evidence Act 1984 (PACE) and the appending Codes of Practice, most notably Code C.

However, the ability of AAs as to perform their role is being impeded by a lack of clarity around their status and the rules that they are governed by. Often at the behest of lawyers, AAs are excluded from the conversations which lawyers have with their clients as a pragmatic solution to the uncertainty in the status of AAs. This means that AAs are rarely able to properly perform their vital role. Consequently, vulnerable people are not receiving the meaningful support they should receive. This represents a missed opportunity to protect the rights and interests of vulnerable people in the criminal justice system. When AAs are deployed effectively and appropriately, they can empower young or vulnerable suspects in an adversarial criminal justice system which, in turn, can help recalibrate the scales of justice to allow for a fairer outcome.

This article will examine and critique the state of the current law, clarify the law on Legal Professional Privilege (LPP) and how that relates to Aas and propose a modest incremental extension to the principles of confidentiality to cover confidential discussions between AAs and young or vulnerable people in the criminal justice system.
Atypical presentations in the hospitalised older adult testing positive for SARS-CoV-2: a retrospective observational study in Glasgow, Scotland
Authors: Davis Peter , Gibson Rory , Wright Emily , Bryan Amy , Ingram Jamie , Lee Ren Ping , Godwin Jon , Evans Tom , Burleigh Elizabeth , Wishart Steven , Capek Eileen , Mitchell Lara
Published: October 2020

Introduction: Understanding of how SARS-CoV-2 manifests itself in older adults was unknown at the outset of the pandemic. We undertook a retrospective observational analysis of all patients admitted to older people’s services with confirmed COVID-19 in one of the largest hospitals in Europe. We detail presenting symptoms, prognostic features and vulnerability to nosocomial spread. Methods: We retrospectively collected data for each patient with a positive SARSCoV-2 RT PCR between 18th March and the 20th April 2020 in a department of medicine for the elderly in Glasgow. Results: 222 patients were included in our analysis. Age ranged from 56 to 99 years (mean = 82) and 148 were female (67%). 119 patients had a positive swab for SARS-CoV-2 within the first 14 days of admission, only 32% of these patients presented with primarily a respiratory type illness. 103 patients (46%) tested positive after 14 days of admission – this was felt to represent likely nosocomial infection. 95 patients (43%) died by day 30 after diagnosis. Discussion: This data indicates that older people were more likely to present with non-respiratory symptoms. High clinical frailty scores, severe lymphopenia and cumulative comorbidities were associated with higher mortality rates. Several contributing factors will have led to nosocomial transmission.
Do School Levels Matter? How Elementary, Middle, and High School Teachers Differ in Their Perceptions and Use of Technology
Authors: Dogan Nihan A. , Dawson Kara , Ritzhaupt Albert D.
Published: October 2020

This study used the Technology Use and Perceptions Survey to explore whether there are differences reported by teachers ( N =  1,287) from elementary, middle, and high schools from a single school district. A two-step data analysis process using multivariate analysis of variance and item-by-item analysis of variance was employed. We used our analyses to generate profiles for elementary, middle, and high school teachers and draw comparisons across these profiles in our discussion. In particular, high school teachers reported the lowest perception of technology’s value and the most infrequent use of technology integration strategies even though they reported their students used technology more frequently. Elementary teachers reported the most frequent use of technology integration strategies and the lowest satisfaction with the access and support they receive. This study supports the need for more research to adequately explore the role of school levels as these differences could provide important insights.
Effects of anthropometric and metabolic parameters on transaminase levels and liver stiffness in patients with non-alcohol fatty liver disease
Authors: Samejo Shoukat Ali , Abbas Zaigham , Asim Muhammad
Published: October 2020

We aimed to investigate 214 patients further with non-alcoholic fatty liver disease (NAFLD) as judged by transient elastography. A body mass index of ≥25 was seen in 172 (80%) of the patients. F2–F4 fibrosis, as depicted by elastography, was present in 114 (53.2%). A Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) of ≥2 was seen in 178 (83.2%). Alanine aminotransferase was elevated in 116 (54%) and aspartate aminotransferase in 88 (41.1%). Liver steatosis was significantly associated with increasing alanine aminotransferase, insulin, HOMA-IR and cholesterol levels. Regression analysis showed cholesterol as a factor independently associated with the degree of liver steatosis. The independent variable related to increasing liver elasticity was steatosis. In conclusion, a significant number of our patients with NAFLD had steatohepatitis and F2–F4 fibrosis.
The influence of father involvement during childhood on the emotional well-being of young adult offspring: a cross-sectional survey of students at a university in Botswana
Authors: Kesebonye Wame Maryjoy , Amone-P’Olak Kennedy
Published: October 2020

Africa is witnessing rapid changes in family structure with noticeable absence and non-involvement of fathers in child-rearing. This study investigated the influence of father involvement in child care on the emotional well-being of young adult offspring in a cross-sectional survey of 375 students (age: M = 21.05 ± 1.94) at a university in Botswana. The Positive Affect and Negative Affect Scale and the Perception of Father Involvement Scale were used to assess emotional well-being and fathers’ involvement, respectively. T-tests, analyses of variance, and regression analyses were used to compute subpopulation differences and the influence of father involvement on emotional well-being. Only 38% of the students lived in a household with both parents, 70% indicated that they have a father figure (biological father, stepfather, uncles, and grandfathers), whereas, 30% of the students indicated that they had had no father figure. The female gender (β = .17, 95% CI = [.07, .27]), father availability (β = .23, 95% CI = [.06, .39]), and responsibility (β = .22, 95% CI = [.07, .27]) significantly and independently predicted emotional well-being. Significant differences were observed between biological father figures and no father figures and between other father figures and no father figure regarding emotional well-being. Father involvement, particularly the domains of availability and responsibility and having a father figure during childhood are associated with better emotional well-being in offspring.
Caregiver–child separation during tuberculosis hospitalisation: a qualitative study in South Africa
Authors: Meyerson Kyla A , Hoddinott Graeme , Garcia-Prats Anthony J , Tomlinson Mark
Published: October 2020

There are an estimated 32,000 incident cases of multidrug-resistant tuberculosis in children globally each year. Extended hospitalisation is often required to ensure optimal adherence to the complex multidrug-resistant tuberculosis treatment regimen. Hospitalisation usually results in caregiver–child separation which is known to cause psychological difficulties in children. We explored caregivers’ and health workers’ perceptions of the effects of caregiver–child separation during hospitalisation for tuberculosis in the Western Cape. We conducted semi-structured interviews with health workers ( n = 7) and caregivers ( n = 14) of children who were receiving multidrug-resistant tuberculosis treatment. All interviews were audio-recorded, transcribed, and translated. We used thematic analysis to organise and interpret the data. We identified three themes: (1) multidrug-resistant tuberculosis treatment was a distressing experience for children, caregivers, and health workers; (2) children’s behavioural states during and post-hospitalisation (e.g., crying, aggression, hyperactivity, and withdrawal) were suggestive of their distress; and (3) caregivers and health workers used strategies, such as deception, threat, and the prioritisation of biomedical health over psychological health as a means to manage their own as well as the children’s distress. This article presents novel research on the dynamics involved in caregiver–child separation as a result of multidrug-resistant tuberculosis treatment in South Africa. We highlight that the challenges of caregiver–child separation intersected with predisposing factors related to the social adversity that families affected by childhood tuberculosis experience. Delivery models that facilitate outpatient community-based care should be prioritised and a more structured form of psychological support should be implemented for those who still require hospitalisation.
Recurrence of endometrial cancer in a hysterectomised patient treated with tamoxifen for breast cancer: a case report
Authors: Woolas James , Davis Megan , Rahimi Siavash
Published: October 2020

Tamoxifen exposure is a recognised risk for primary endometrial cancer. This case serves as a reminder to meticulously check the past medical history and inform patients of the risk-benefit of treatment as part of a shared-decision making process.