bluuebunny/crossref_metadata_2025 huggingface dataset:
Agrobacterium-delivered VirE2 interacts with host nucleoporin CG1 to facilitate the nuclear import of VirE2-coated T complex
Authors: Li Xiaoyang , Yang Qinghua , Peng Ling , Tu Haitao , Lee Lan-Ying , Gelvin Stanton B. , Pan Shen Q.
Published: October 2020

Significance

Molecular trafficking into nuclei is essential for eukaryotic cells. However, it is not clear how a large linear protein complex enters the nucleus in a natural setting.Agrobacteriumdelivers T-DNA along with the protein VirD2 and perhaps VirE2 into the host nucleus. Here, we report that VirD2 provides the guide on the “head” and VirE2 provides the lateral assistance to facilitate nuclear import of the T-DNA–protein complex. VirE2 directly interacts with the host nuclear pore complex component nucleoporin CG1 to facilitate nuclear uptake of the T-complex and the transformation process. Our findings shed light on how a pathogen delivers large linear nucleoprotein complexes into host nuclei.
Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria
Authors: Mor Danielle E. , Sohrabi Salman , Kaletsky Rachel , Keyes William , Tartici Alp , Kalia Vrinda , Miller Gary W. , Murphy Coleen T.
Published: October 2020

Significance

Uncovering the role of defective metabolism in Parkinson’s disease (PD) may lead to the discovery of disease-modifying therapies. We recently linked branched-chain amino acid (BCAA) metabolism with PD, yet the underlying mechanisms were unknown. We now report the unexpected finding that BCAA metabolic dysfunction causes Parkinson’s-like motor deficits and neurodegeneration by inducing a state of hyperactive mitochondria. We found that the type 2 diabetes medication metformin is able to rescue neuronal viability by reducing mitochondrial respiration. These results offer mitochondrial hyperactivity as a new potential mechanism of mitochondrial dysfunction in Parkinson’s disease, and suggest that efforts to reduce mitochondrial respiration early in the disease—potentially by metformin treatment—may be efficacious.
Exploring the activation pathway and G
i
-coupling specificity of the μ-opioid receptor
Authors: Mondal Dibyendu , Kolev Vesselin , Warshel Arieh
Published: October 2020

Significance

A detailed molecular-level understanding of the mechanism of activation and coupling selectivity of the μ-opioid receptor (μ-OR) is largely missing in the literature, despite remarkable advances in structural and biochemical studies. Here we have performed extensive free energy calculations using our electrostatic-based coarse-grained model and obtained a complete thermodynamic cycle and two-dimensional free energy landscapes for the activation process. This allowed us to propose a plausible sequence of events that drives the activation process. Additionally, we have been able to explain the selectivity of the coupling between μ-OR and G proteins, by using free energy calculations. This advance can serve as a basis for further progress in understanding the biased signaling of μ-OR.
Metallization of diamond
Authors: Shi Zhe , Dao Ming , Tsymbalov Evgenii , Shapeev Alexander , Li Ju , Suresh Subra
Published: October 2020

Significance

Identifying the conditions for complete metallization of diamond solely through mechanical strain is an important scientific objective and technological demonstration. Through quantum mechanical calculations, continuum mechanics simulations validated by experiments, and machine learning, we show here that reversible metallization can be achieved in diamond deformed below threshold elastic strain levels for failure or phase transformation. The general method outlined here for deep elastic strain engineering is also applicable to map the strain conditions for indirect-to-direct bandgap transitions. Our method and findings enable extreme alterations of semiconductor properties via strain engineering for possible applications in power electronics, optoelectronics, and quantum sensing.
Layer-dependent topological phase in a two-dimensional quasicrystal and approximant
Authors: Cain Jeffrey D. , Azizi Amin , Conrad Matthias , Griffin Sinéad M. , Zettl Alex
Published: October 2020

Significance

The behavior of electrons in solids is intimately related to symmetry and dimensionality, and it is the interaction of these two that dictates the topological properties of materials. Here, we study this by introducing quasiperiodic order into a two-dimensional material, expanding the catalogue topological systems to include quasicrystals. Specifically, we report the isolation and investigation of a two-dimensional chalcogenide quasicrystal and approximant, ∼Ta
1.6
Te, derived from a layered transition metal dichalcogenide. Density functional theory of a large unit cell approximant demonstrates that the material possesses a layer-tunable, topologically nontrivial band structure, hitherto unseen in quasicrystalline materials. This work lays the foundation for the study of the interrelated properties of dimensionality, topology, and symmetry in van der Waals solids and heterostructures.
An inhibitor of endothelial ETS transcription factors promotes physiologic and therapeutic vessel regression
Authors: Schafer Christopher M. , Gurley Jami M. , Kurylowicz Katarzyna , Lin Prisca K. , Chen Wen , Elliott Michael H. , Davis George E. , Bhatti Faizah , Griffin Courtney T.
Published: October 2020

Significance

Premature babies and diabetic patients can become blind when too many blood vessels develop in their eyes, and therapeutic strategies are needed for eliminating those extra vessels. We studied newborn mice that naturally undergo loss of some eye vessels to identify ways to promote blood vessel regression and elimination. We identified a class of proteins called E-26 transformation-specific transcription factors that are downregulated during normal vessel regression, especially in vessels with slow blood flow. Importantly, we found that a drug that disables these proteins can be used in mouse eyes to eliminate abnormal, slow-flow blood vessels similar to those seen in premature babies and diabetic patients.
Normal levels of ribosome-associated chaperones cure two groups of [PSI+] prion variants
Authors: Son Moonil , Wickner Reed B.
Published: October 2020

Significance

[PSI+] is a prion (infectious protein) form of the yeast Sup35 protein, propagating as an amyloid filamentous polymer. We find that each of the ribosome-associated chaperones—Ssb1/2p, Zuo1p, and Ssz1p—at their normal expression levels, blocks [PSI+] generation and the propagation of most new [PSI+] prion variants generated in their absence. The curing mechanism involves the functional triad of ribosome-associated chaperones. Our results suggest that cells do not want to have a prion: Cells reduce the chance of a prion emerging at the polypeptide level, and usually immediately cure those prions that do arise perhaps by limiting fiber growth.
Structural evolution of heavy rare Earth-based metal glass under high pressure
Authors: Yongyong Wang , Panpan Zhang , Qing Li , Gong Li
Published: October 2020

The structural evolution of Er55Al25Co20 metallic glasses (MGs) at high pressure was studied through x-ray diffraction with synchrotron radiation. The compression ratio, differential structure factor, pair distribution function g(r), and relative resistance as functions of pressure were analyzed and discussed. A reversible polyamorphic transition with a clear hysteresis was detected in the Er55Al25Co20 MGs. The irreversible annihilation of free volume and voids led to a densification of the specimens. Electronic resistance measurements demonstrated that the transition was strongly correlated with the electronic structural evolution. The results provide a new insight into understanding the mechanisms of polyamorphism in MGs.
STARCH: copy number and clone inference from spatial transcriptomics data
Authors: Elyanow Rebecca , Zeira Ron , Land Max , Raphael Benjamin J
Published: October 2020

Tumors are highly heterogeneous, consisting of cell populations with both transcriptional and genetic diversity. These diverse cell populations are spatially organized within a tumor, creating a distinct tumor microenvironment. A new technology called spatial transcriptomics can measure spatial patterns of gene expression within a tissue by sequencing RNA transcripts from a grid of spots, each containing a small number of cells. In tumor cells, these gene expression patterns represent the combined contribution of regulatory mechanisms, which alter the rate at which a gene is transcribed, and genetic diversity, particularly copy number aberrations (CNAs) which alter the number of copies of a gene in the genome. CNAs are common in tumors and often promote cancer growth through upregulation of oncogenes or downregulation of tumor-suppressor genes. We introduce a new method STARCH (spatial transcriptomics algorithm reconstructing copy-number heterogeneity) to infer CNAs from spatial transcriptomics data. STARCH overcomes challenges in inferring CNAs from RNA-sequencing data by leveraging the observation that cells located nearby in a tumor are likely to share similar CNAs. We find that STARCH outperforms existing methods for inferring CNAs from RNA-sequencing data without incorporating spatial information.
Feedback-aided data acquisition improves myoelectric control of a prosthetic hand
Authors: Gigli Andrea , Brusamento Donato , Meattini Roberto , Melchiorri Claudio , Castellini Claudio
Published: October 2020

Objective. Pattern-recognition-based myocontrol can be unreliable, which may limit its use in the clinical practice and everyday activities. One cause for this is the poor generalization of the underlying machine learning models to untrained conditions. Acquiring the training data and building the model more interactively can reduce this problem. For example, the user could be encouraged to target the model’s instabilities during the data acquisition supported by automatic feedback guidance. Interactivity is an emerging trend in myocontrol of upper-limb electric prostheses: the user should be actively involved throughout the training and usage of the device.

Approach. In this study, 18 non-disabled participants tested two novel feedback-aided acquisition protocols against a standard one that did not provide any guidance. All the protocols acquired data dynamically in multiple arm positions to counteract the limb position effect. During feedback-aided acquisition, an acoustic signal urged the participant to hover with the arm in specific regions of her peri-personal space, de facto acquiring more data where needed. The three protocols were compared on everyday manipulation tasks performed with a prosthetic hand. Main results. Our results showed that feedback-aided data acquisition outperformed the acquisition routine without guidance, both objectively and subjectively. Significance. This indicates that the interaction with the user during the data acquisition is fundamental to improve myocontrol.
Material modifications enhancing the antibacterial properties of two biodegradable poly(3-hydroxybutyrate) implants
Authors: Ferlic P W , Nogler M , Weinberg A M , Kühn K D , Liebensteiner M , Coraça-Huber D C
Published: October 2020

The aim of this study was to evaluate the antimicrobial efficacy of adding a gentamicin palmitate (GP) coating and zirconium dioxide (ZrO2) to biodegradable poly(3-hydroxybutyrate) (PHB) to reduce biofilm formation. Cylindrical pins with and without a coating were incubated in Müller-Hinton broth inoculated with 2 × 105 colony-forming units (CFU) ml-1 of Staphylococcus aureus for 2 d or 7 d, then sonicated to disrupt biofilms. Pure PHB (PHB + GP) and PHB pins with ZrO2 added (PHBzr + GP) were coated with GP and compared with PHB pins lacking a coating (PHB). Cells (CFU) were counted to quantify the number of bacteria in the biofilm and a cell proliferation assay was employed to evaluate metabolic activity, and scanning electron microscopy (SEM) was performed to visualize the structure of the biofilm. After 2 d of incubation there were significantly more cells in biofilms on PHB pins than PHB + GP and PHBzr + GP pins (p < 0.0001), and cells in the sonication fluid obtained from GP-coated pins exhibited significantly lower metabolic activity than cells from uncoated PHB pins (p < 0.0001). After 7 d of incubation metabolic activity was lowest for PHBzr + GP, with significant differences between PHB and PHBzr + GP (p = 0.001). SEM revealed more cells attached to the surface, and more structured biofilms, on pins without a coating. Coating pins with GP significantly reduced early biofilm formation on PHB implants. This could lower the potential risk of surgical site infections when using PHB implants. Addition of ZrO2 might further enhance the antibacterial properties. Such modification of the implant material should therefore be considered when developing new biodegradable PHB implants.
Delivery of dimethyloxalylglycine in calcined bone calcium scaffold to improve osteogenic differentiation and bone repair
Authors: Weng Tujun , Zhou Liangliang , Yi Lingxian , Zhang Chunli , He Ying , Wang Tianqi , Ju Yue , Xu Ye , Li Li
Published: October 2020

As hypoxia plays a vital role in the angiogenic-osteogenic coupling, using proline hydroxylase inhibitors to manipulate hypoxia-inducible factors has become a strategy to improve the osteogenic properties of biomaterials. Dimethyloxallyl glycine (DMOG) is a 2-ketoglutarate analog, a small molecular compound that competes for 2-ketoglutaric acid to inhibit proline hydroxylase. In order to improve the osteogenic ability of calcined bone calcium (CBC), a new hypoxia-mimicking scaffold (DMOG/Collagen/CBC) was prepared by immersing it in the DMOG-Collagen solution, followed by freeze-drying. All coated CBC scaffolds retained the inherent natural porous architecture and showed excellent biocompatibility. A slow release of DMOG by the DMOG-loaded CBC scaffolds for up to one week was observed in in vitro experiments. Moreover, the DMOG/Collagen/CBC composite scaffold was found to significantly stimulate bone marrow stromal cells to express osteogenic and angiogenic genes in vitro. In addition, the osteogenic properties of three kinds of scaffolds, raw CBC, Collagen/CBC, and DMOG/Collagen/CBC, were evaluated by histology using the rabbit femoral condyle defect model. Histomorphometric analyses showed that the newly formed bone (BV/TV) in the DMOG/Collagen/CBC group was significantly higher than that of the Collagen/CBC group. However, immunostaining of CD31 and Runx2 expression between these two groups showed no significant difference at this time point. Our results indicate that DMOG-coated CBC can promote osteogenic differentiation and bone healing, and show potential for clinical application in bone tissue engineering.
Smart releasing electrospun nanofibers—poly: L.lactide fibers as dual drug delivery system for biomedical application
Authors: Wulf Katharina , Arbeiter Daniela , Matschegewski Claudia , Teske Michael , Huling Jennifer , Schmitz Klaus-Peter , Grabow Niels , Kohse Stefanie
Published: October 2020

An ongoing challenge in drug delivery systems for a variety of medical applications, including cardiovascular diseases, is the delivery of multiple drugs to address numerous phases of a treatment or healing process. Therefore, an extended dual drug delivery system (DDDS) based on our previously reported cardiac DDDS was generated. Here we use the polymer poly(L-lactide) (PLLA) as drug carrier with the cytostatic drug Paclitaxel (PTX) and the endothelial cell proliferation enhancing growth factor, human vascular endothelial growth factor (VEGF), to overcome typical in-stent restenosis complications. We succeeded in using one solution to generate two separate DDDS via spray coating (film) and electrospinning (nonwoven) with the same content of PTX and the same post processing for VEGF immobilisation. Both processes are suitable as coating techniques for implants. The contact angle analysis revealed differences between films and nonwovens. Whereas, the morphological analysis demonstrated nearly no changes occurred after immobilisation of both drugs. Glass transition temperatures (Tg
) and degree of crystallinity (χ) show only minor changes. The amount of immobilised VEGF on nonwovens was over 300% higher compared to the films. Also, the nonwovens revealed a much faster and over three times higher PTX release over 70 d compared to the films. The almost equal physical properties of nonwovens and films allow the comparison of both DDDS independently of their fabrication process. Both films and nonwovens have significantly increased in vitro cell viability for human umbilical vein endothelial cells (EA.hy926) with dual loaded PTX and VEGF compared to PTX-only loaded samples.
On non-steady planar motions of fibre-reinforced fluids. Geometry and integrable structure
Authors: Demskoi D K , Schief W K
Published: October 2020

It is shown that the kinematic system describing planar non-steady motions of ideal fibre-reinforced fluids may be reduced to a single two-dimensional third-order partial differential equation in which time enters parametrically. A procedure is established which maps steady motions to non-steady motions. The resulting motions inherit their hidden integrable structure from the steady case. The formalism presented here also readily recovers the connection with the scattering problem of the modified Korteweg–de Vries (mKdV) hierarchy established in previous work.
Race/Ethnicity, Cumulative Midlife Loss, and Carotid Atherosclerosis in Middle-Aged Women
Authors: Lewis Tené T , Van Dyke Miriam E , Matthews Karen A , Barinas-Mitchell Emma
Published: October 2020

African-American women have elevated rates of cardiovascular disease compared with women of other races or ethnicities, and race/ethnicity–related stressors may play a role. We examined the association between a race/ethnicity–related stressor, midlife loss, and a marker of cardiovascular risk, carotid intima media thickness (IMT), in 1,410 African-American, White, Chinese, and Hispanic women from the Study of Women’s Health Across the Nation. Participants were queried about losses annually over 12 years (1996–2013), with IMT assessed in year 12–13 via ultrasound. Linear regression models were used to examine associations between cumulative upsetting losses and IMT, adjusting for covariates. In minimally adjusted models in the full cohort, 3 or more upsetting losses (vs. none) were associated with IMT (β = 0.03, 95% confidence interval (CI): 0.01, 0.05; P = 0.0003). Results were more robust among African-American women (β = 0.042, 95% CI: 0.01, 0.07; P < 0.01) than White (β = 0.014, 95% CI: –0.01, 0.03; P = 0.21), Chinese (β = 0.036, 95% CI: –0.03, 0.10; P = 0.25), or Hispanic (β = 0.036, 95% CI: –0.07, 0.14; P = 0.51) women, although associations among women from racial/ethnic minorities overall were of similar magnitude. Results persisted in fully adjusted models (P for interaction with race/ethnicity = 0.04). Midlife loss may be a pathway through which race/ethnicity influences cardiovascular risk for African-American women and, potentially, Chinese and Hispanic women.
L1 versus Dominant Language Transfer Effects in L2 and Heritage Speakers of Italian: A Structural Priming Study
Authors: Romano Francesco
Published: October 2020

Conversely to plenty of studies describing how L1 transfer affects L2 systems, where the two grammars, L1/L2, often only come to interact later in life, less is known of dominant language transfer in heritage language grammars. Unlike in L2 speakers, the dominant language of the heritage speaker potentially affects its weaker language already from childhood. Evidence of dominant language transfer, however, exists in language production studies focusing on syntax. Therefore, an oral structural priming task was employed to compare transfer effects in advanced Swedish speakers of Italian and early heritage Italian speakers dominant in Swedish. Intrinsic to this comparison is the Basic Continuity hypothesis (Romano 2018), which proposes that highly proficient L2 speakers integrate semantic and syntactic information relevant to an L2 property lacking in the L1 in native-like ways. Results showed that heritage and L2 grammars are similarly impervious to transfer effects and coordinate structural and lexico-semantic information in native-like ways, consistent with the Basic Continuity. Divergence from native controls is shown to be remarkably compatible with monolingual grammars at earlier developmental stages.
Quantifying diagnostic accuracy improvement of new biomarkers for competing risk outcomes
Authors: Wang Zheng , Cheng Yu , Seaberg Eric C , Becker James T
Published: October 2020

The net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) were originally proposed to characterize accuracy improvement in predicting a binary outcome, when new biomarkers are added to regression models. These two indices have been extended from binary outcomes to multi-categorical and survival outcomes. Working on an AIDS study where the onset of cognitive impairment is competing risk censored by death, we extend the NRI and the IDI to competing risk outcomes, by using cumulative incidence functions to quantify cumulative risks of competing events, and adopting the definitions of the two indices for multi-category outcomes. The “missing” category due to independent censoring is handled through inverse probability weighting. Various competing risk models are considered, such as the Fine and Gray, multistate, and multinomial logistic models. Estimation methods for the NRI and the IDI from competing risk data are presented. The inference for the NRI is constructed based on asymptotic normality of its estimator, and the bias-corrected and accelerated bootstrap procedure is used for the IDI. Simulations demonstrate that the proposed inferential procedures perform very well. The Multicenter AIDS Cohort Study is used to illustrate the practical utility of the extended NRI and IDI for competing risk outcomes.
Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury
Authors: Zrzavy Tobias , Schwaiger Carmen , Wimmer Isabella , Berger Thomas , Bauer Jan , Butovsky Oleg , Schwab Jan M , Lassmann Hans , Höftberger Romana
Published: October 2020

Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration).
Frequency of Routine Testing for Coronavirus Disease 2019 (COVID-19) in High-risk Healthcare Environments to Reduce Outbreaks
Authors: Chin Elizabeth T , Huynh Benjamin Q , Chapman Lloyd A C , Murrill Matthew , Basu Sanjay , Lo Nathan C
Published: October 2020

Routine asymptomatic testing strategies for COVID-19 have been proposed to prevent outbreaks in high-risk healthcare environments. We used simulation modeling to evaluate the optimal frequency of viral testing. We found that routine testing substantially reduces risk of outbreaks, but may need to be as frequent as twice weekly.
Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus–1
Authors: Riddler Sharon A , Para Michael , Benson Constance A , Mills Anthony , Ramgopal Moti , DeJesus Edwin , Brinson Cynthia , Cyktor Joshua , Jacobs Jana , Koontz Dianna , Mellors John W , Laird Gregory M , Wrin Terri , Patel Heena , Guo Susan , Wallin Jeffrey , Boice Jillian , Zhang Liao , Humeniuk Rita , Begley Rebecca , German Polina , Graham Hiba , Geleziunas Romas , Brainard Diana M , SenGupta Devi
Published: October 2020

Background

Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)–1.

Methods

In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6–10 doses of vesatolimod (1–12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives.

Results

A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug–related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.

Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon–inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values.

Conclusions

Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV.

Clinical Trials Registration

NCT02858401.
Reinvestigating the London ‘Hooligan’ Panic of 1898
Authors: Davies Andrew
Published: October 2020

This article examines the agency of a group previously neglected by historians: the so-called ‘folk devils’ of historical moral panics. Orthodox studies of moral panics foreground the role of the mass media in creating folk devils, along with the responses of agents such as the police and the courts. This article takes a different approach, by examining the lived experience of folk devils themselves. It focuses on the London ‘Hooligan’ scare of 1898. Using the example of John D’Arcy, an eighteen-year-old from South London, who came to embody the Hooligan threat following his conviction for murder, it explores how a prominent folk devil and his family sought to negotiate, and refute, his demonisation by a sensation-hungry press. Two letters written by D’Arcy in prison enable us to give voice to a Hooligan for the first time. These demonstrate D’Arcy’s understanding of, and his attempt to refute, his demonisation, and his subsequent representation of himself as a humble, pious penitent. This study offers a new perspective on the class dynamics of late Victorian society, by showing how the D’Arcys, in alliance with the prominent prison visitor Katharine Parr, Irish Nationalist MPs and the medical officer at Parkhurst convict prison, effectively mobilised the rhetoric of moral reformation as they strove to free John from the stigma attached to him during an episode of moral panic.
Risk of postoperative neurological exacerbation in patients with infective endocarditis and intracranial haemorrhage
Authors: Diab Mahmoud , Musleh Rita , Lehmann Thomas , Sponholz Christoph , Pletz Mathias W , Franz Marcus , Schulze P Christian , Witte Otto W , Kirchhof Klaus , Doenst Torsten , Günther Albrecht
Published: October 2020

OBJECTIVES

Cardiac surgery in patients with infective endocarditis (IE) and preoperative intracranial haemorrhage (pre-ICH) is a highly debatable issue, and guidelines are still not well defined. The goal of this study was to investigate the effect of cardiac surgery and its timing on the clinical outcomes of patients with IE and pre-ICH.

METHODS

We did a single-centre retrospective analysis of data from patients with preoperative brain imaging who had surgery for left-sided IE between January 2007 and May 2018.

RESULTS

Among the 363 patients included in the study, 34 had pre-ICH. Hospital mortality was similar between the patients with and without pre-ICH (29% vs 27%, respectively; P = 0.84). Unadjusted, postoperative neurological deterioration appeared higher in patients with pre-ICH (24% vs 17%; P = 0.35). In multivariable analysis, pre-ICH did not qualify as an independent predictor for either postoperative neurological deterioration [odds ratio 1.10, 95% confidence interval (CI) 0.44–2.73; P = 0.84] or hospital mortality (odds ratio 1.02, 95% CI 0.43–2.40; P = 0.96). Postoperative partial thromboplastin time was significantly elevated in 4 patients with relevant post-ICH compared with those patients without relevant post-ICH (65.5 vs 37.6, respectively; P = 0.004).

CONCLUSIONS

Pre-ICH was not an independent predictor for postoperative neurological deterioration or hospital mortality in patients with IE. Postoperative coagulation management seems to be crucial in patients with IE with ICH. Although this is to date the largest monocentric study addressing surgical decision and timing, the number of patients with pre-ICH was low. Therefore, these conclusions should be regarded with caution; randomized clinical trials are needed.
The journey of omega-3 fatty acids in cardiovascular medicine
Authors: Ferrari Roberto , Censi S , Cimaglia P
Published: October 2020

In subjects with cardiovascular risk factors or in patients in need of secondary prevention, hypertriglyceridemia is a well-defined risk factor for adverse cardiac events. Drugs containing n-3 polyunsaturated fatty acids (n-3 PUFAs) are approved for treatment of hypertriglyceridemia. In 1999, a cardioprotective effect in post infarct patients was suggested by a large multicentre study, the GISSI prevention trial. The hypothesized mechanism of action was an antiarrhythmic action leading to reduction of the sudden death. However, such a cardioprotective effect of n-3 PUFAs has not been straightforward like for other cardiovascular drugs such as aspirin, statins or ACE inhibitors. On the contrary, it has been a long journey with several ups and downs. Recently, the European Medicines Agency (EMA) has not confirmed the risk benefit of low dose of n-3 PUFA in preventing outcomes after a myocardial infarction. Since the EMA decision, the use of a high dose (4g daily) of pure and stable EPA in a multicentre, international trial, the REDUCE-IT study showed a clear cardiovascular event reduction which was not confirmed in another trial, the STRENGTH study, which utilized 4g daily of an EPA+DHA mixture. It follows that the OMEGA-3 fatty acid story seems to be endless and the last word on cardiovascular benefits cannot be pronounced. We report a brief narrative of an entire journey from the beginning to nowadays.
Beyond cardiovascular medicine: potential future uses of icosapent ethyl
Authors: Bhatt Deepak L , Hull Mark A , Song Mingyang , Van Hulle Carol , Carlsson Cindy , Chapman M John , Toth Peter P
Published: October 2020

The REDUCE-IT trial demonstrated that icosapent ethyl, an ethyl ester of eicosapentaenoic acid (EPA), reduced cardiovascular events in an at-risk population by a substantial degree. While the cardiovascular protective properties of this compound are now proven, several other potential uses are being actively explored in clinical studies. These areas of investigation include cancer, inflammatory bowel disease, infections, Alzheimer’s disease, dementia, and depression. The next decade promises to deepen our understanding of the beneficial effects that EPA may offer beyond cardiovascular risk reduction.
A UK local seismic magnitude scale, MLP, using P-wave amplitudes
Authors: Green David N , Luckett Richard , Baptie Brian , Bowers David
Published: October 2020

A local seismic magnitude scale, MLP, has been developed for the United Kingdom (UK) using automated measurements of 8902 half peak-to-peak vertical component seismic P-wave displacement amplitudes from 630 earthquakes. The measurement time window increases with source-to-receiver range such that MLP is sensitive to the dominant phase within the P-wavetrain at a given distance. To avoid contamination due to low-frequency noise, the P-wave amplitude measurements are made in the 1.5–30 Hz passband. A least-squares inversion was undertaken to estimate source size, distance and station effects. The distance effect values suggest that P-wave amplitude attenuation across the UK is low when compared to other tectonically stable regions. The station effects are broadly consistent with UK geology, with signal amplification observed within the sediments towards the south-east of the country. MLP has been tied to the UK local magnitude scale routinely estimated by the British Geological Survey (BGS, determined using S waves, and here denoted MLBGS). For earthquakes with MLBGS > 3, MLP exhibits a closer correspondence to the moment magnitude than MLBGS (i.e. MLP≈Mw). It is tentatively suggested that this reduction in bias is caused by the P-wave scale being less affected by along-path attenuation. The difference with respect to physical source scaling helps explain the divergence of the MLBGS and MLP scales at ML > 3. MLP allows a robust estimate of event size to be made for small events which predominantly generate P waves, for example, near-surface explosions. MLP values have been calculated for 239 explosive events, mostly mining blasts and munitions disposal. Although there is significant scatter, explosive events exhibit elevated MLP values compared to MLBGS, consistent with explosions generating proportionally more compressional wave energy than earthquakes. For example, 33 explosions at sea exhibit a median MLP–MLBGS value of 0.50 mag units. Despite its sensitivity to P-wave amplitude, MLP is not a more consistent estimator of explosive source size than MLBGS; the magnitude residuals (station estimate − event estimate) are slightly less for MLBGS compared to MLP. This is primarily due to variability of the P-wave amplitudes that cannot be explained by a 1-D distance correction. MLP should be considered as an additional tool for characterizing small seismic events within the UK.
After They Left: Looted Jewish Apartments and the Private Perception of the Holocaust
Authors: Dorothée Lange Carolin
Published: October 2020

This study of the afterlife of “abandoned” Jewish property in National Socialist Germany analyzes the emotional impact on Jewish families of the loss of personal belongings, and those belongings’ emotional impact on the Gentile families that acquired them. This property could be movable and intimate: jewelry, furniture, porcelain, and the like; as well as immovable: apartments and houses illegitimately wrested from their residents or owners. The author asks how Gentiles’ behavior changed in relation to the escalating Holocaust of the Jews. She argues that the reactions of both ordinary Germans and government authorities changed when the mass deportations started, indicating that non-Jewish Germans were very much aware of the experience of their Jewish neighbors.
A class of optimal control problems governed by singular systems via Balakrishnan’s method
Authors: Makreloufi Abed , Benharrat Mohammed
Published: October 2020

The purpose of this paper is to discuss, by the use of the Balakrishnan’s epsilon method, a class of optimal control problems governed by continuous linear time invariant singular systems which have only a finite dynamic mode. The linear differential algebraic equation is handled using the epsilon technique to obtain a sequence of the calculus of variations problems. A convergence theorem is given to obtain approximate and, in the limit, an optimal solution of this class of optimal control problem by the use of the necessary optimality conditions of Euler–Lagrange type. A correspondence has been also shown between this penalty function and duality for this class of optimal control problems considered. As an application, an example of optimal linear quadratic problem is also given.
d-elliptic Loci in Genus 2 and 3
Authors: Lian Carl
Published: October 2020

We consider the loci of curves of genus 2 and 3 admitting a $d$-to-1 map to a genus 1 curve. After compactifying these loci via admissible covers, we obtain formulas for their Chow classes, recovering results of Faber–Pagani and van Zelm when $d=2$. The answers exhibit quasimodularity properties similar to those in the Gromov–Witten theory of a fixed genus 1 curve; we conjecture that the quasimodularity persists in higher genus and indicate a number of possible variants.
Reversion of Pneumolysin-Induced Executioner Caspase Activation Redirects Cells to Survival
Authors: Nerlich Andreas , von Wunsch Teruel Iris , Mieth Maren , Hönzke Katja , Rückert Jens C , Mitchell Timothy J , Suttorp Norbert , Hippenstiel Stefan , Hocke Andreas C
Published: October 2020

Apoptosis is an indispensable mechanism for eliminating infected cells and activation of executioner caspases is considered to be a point of no return. Streptococcus pneumoniae, the most common bacterial pathogen causing community-acquired pneumonia, induces apoptosis via its pore-forming toxin pneumolysin, leading to rapid influxes of mitochondrial calcium [Ca2+]m as well as fragmentation, and loss of motility and membrane potential, which is accompanied by caspase-3/7 activation. Using machine-learning and quantitative live-cell microscopy, we identified a significant number of alveolar epithelial cells surviving such executioner caspase activation after pneumolysin attack. Precise single-cell analysis revealed the [Ca2+]m amplitude and efflux rate as decisive parameters for survival and death, which was verified by pharmacological inhibition of [Ca2+]m efflux shifting the surviving cells towards the dying fraction. Taken together, we identified the regulation of [Ca2+]m as critical for controlling the cellular fate under pneumolysin attack, which might be useful for therapeutic intervention during pneumococcal infection.
Rapid, Sensitive, and Specific Severe Acute Respiratory Syndrome Coronavirus 2 Detection: A Multicenter Comparison Between Standard Quantitative Reverse-Transcriptase Polymerase Chain Reaction and CRISPR-Based DETECTR
Authors: Brandsma Eelke , Verhagen Han J M P , van de Laar Thijs J W , Claas Eric C J , Cornelissen Marion , van den Akker Emile
Published: October 2020

Background

Recent advances in CRISPR-based diagnostics suggest that DETECTR, a combination of reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) and subsequent Cas12 bystander nuclease activation by amplicon-targeting ribonucleoprotein complexes, could be a faster and cheaper alternative to quantitative reverse-transcription polymerase chain reaction (qRT-PCR) without sacrificing sensitivity and/or specificity.

Methods

In this study, we compare DETECTR with qRT-PCR to diagnose coronavirus disease 2019 on 378 patient samples. Patient sample dilution assays suggest a higher analytical sensitivity of DETECTR compared with qRT-PCR; however, this was not confirmed in this large patient cohort, where we report 95% reproducibility between the 2 tests.

Results

These data showed that both techniques are equally sensitive in detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) providing additional value of DETECTR to the currently used qRT-PCR platforms. For DETECTR, different guide ribonucleic acids can be used simultaneously to obviate negative results due to mutations in N-gene. Lateral flow strips, suitable as a point-of-care test, showed a 100% correlation to the high-throughput DETECTR assay. More importantly, DETECTR was 100% specific for SARS-CoV-2 relative to other human coronaviruses.

Conclusions

Because there is no need for specialized equipment, DETECTR could be rapidly implemented as a complementary technically independent approach to qRT-PCR thereby increasing the testing capacity of medical microbiological laboratories and relieving the existent PCR platforms for routine non-SARS-CoV-2 diagnostic testing.
The effect of electronic audits and feedback in primary care and factors that contribute to their effectiveness: a systematic review
Authors: Van Den Bulck Steve , Spitaels David , Vaes Bert , Goderis Geert , Hermens Rosella , Vankrunkelsven Patrik
Published: October 2020

Purpose

The aim of this systematic review was (i) to assess whether electronic audit and feedback (A&F) is effective in primary care and (ii) to evaluate important features concerning content and delivery of the feedback in primary care, including the use of benchmarks, the frequency of feedback, the cognitive load of feedback and the evidence-based aspects of the feedback.

Data sources

The MEDLINE, Embase, CINAHL and CENTRAL databases were searched for articles published since 2010 by replicating the search strategy used in the last Cochrane review on A&F.

Study selection

Two independent reviewers assessed the records for their eligibility, performed the data extraction and evaluated the risk of bias. Our search resulted in 8744 records, including the 140 randomized controlled trials (RCTs) from the last Cochrane Review. The full texts of 431 articles were assessed to determine their eligibility. Finally, 29 articles were included.

Data extraction

Two independent reviewers extracted standard data, data on the effectiveness and outcomes of the interventions, data on the kind of electronic feedback (static versus interactive) and data on the aforementioned feedback features.

Results of data synthesis

Twenty-two studies (76%) showed that electronic A&F was effective. All interventions targeting medication safety, preventive medicine, cholesterol management and depression showed an effect. Approximately 70% of the included studies used benchmarks and high-quality evidence in the content of the feedback. In almost half of the studies, the cognitive load of feedback was not reported. Due to high heterogeneity in the results, no meta-analysis was performed.

Conclusion

This systematic review included 29 articles examining electronic A&F interventions in primary care, and 76% of the interventions were effective. Our findings suggest electronic A&F is effective in primary care for different conditions such as medication safety and preventive medicine. Some of the benefits of electronic A&F include its scalability and the potential to be cost effective. The use of benchmarks as comparators and feedback based on high-quality evidence are widely used and important features of electronic feedback in primary care. However, other important features such as the cognitive load of feedback and the frequency of feedback provision are poorly described in the design of many electronic A&F intervention, indicating that a better description or implementation of these features is needed. Developing a framework or methodology for automated A&F interventions in primary care could be useful for future research.
Lessons Learned From Two Survivors of Greater Than 90% TBSA Full-Thickness Burn Injuries Using NovoSorb Biodegradable Temporizing Matrix™ and Autologous Skin Cell Suspension, RECELL™: A Case Series
Authors: Malkoc Aldin , Wong David T
Published: October 2020

Since autologous split-thickness skin grafts are scarce and lab skin growth requires a significant amount of time, there are limited available treatment approaches for patients with full-thickness burns greater than 90% TBSA. Additionally, to achieve the primary goal of skin coverage and resuscitation, there must exist a balance between fluid loss and metabolic derangement. Allografts and xenografts have traditionally been used early in the process to achieve these goals. Currently, novel approaches to treatment consider the additional use of synthetic dermal substitutes and autologous skin cell suspension to improve outcomes. This case series describes the treatment course of patients with greater than 90% TBSA full-thickness burn injuries using a staged, multifaceted approach of using NovoSorb Biodegradable Temporizing Matrix™ as the primary dermal substitute in conjunction with a RECELL™ Autologous Cell Suspensions Device applied with autograft and allograft to achieve improved resuscitation, limiting fluid loss, and finally skin coverage. Allograft and NovoSorb Biodegradable Temporizing Matrix™ were used early to cover excised burns, resulting in improved metabolic control by limiting the systemic inflammatory response syndrome and fluid loss. Both patients survived using this approach.
Framing and legitimating EU legal regulation of human gene-editing technologies: key facets and functions of an imaginary
Authors: Mahalatchimy Aurélie , Lau Pin Lean , Li Phoebe , Flear Mark L
Published: October 2020

Gene-editing technologies, ie those able to make changes in the DNA of an organism, are the object of global competition and a regulatory race between countries and regions. There is an attempt to craft legal frameworks protective enough for users, but flexible enough for developers of gene-editing technologies. This article examines the imaginary built into the framing of EU-level legal regulation of human gene-editing technologies and identifies its three key related facets: the tension around naturalness; safeguarding morality and ethics; and the pursuit of medical objectives for the protection of human health. Concerns around the use of gene-editing technologies in relation to eugenics and human enhancement have produced a multifaceted imaginary. We argue that this imaginary not only places a limit on EU-level regulation, despite a strong EU competence in respect of the internal market, but also seeks to ensure its legitimation.
Incidental finding of heterotopic supradiaphragmatic liver
Authors: Jhamb Shaurya , Pillai Harshil , Maguire Christopher , Palamuthusingam Pranavan
Published: October 2020

Here we describe a case of heterotopic, supradiaphragmatic liver in a 65-year-old woman who was referred for investigation of a soft tissue gallbladder mass. Contrast-enhanced magnetic resonance imaging revealed adenomyomatosis of the gallbladder and supradiaphragmatic accessory liver tissue. This is a remarkably rare normal variant.