bluuebunny/crossref_metadata_2025 huggingface dataset:
Medication as a risk factor for hospitalization due to heart failure and shock: a series of case-crossover studies in Swiss claims data
Authors: Jödicke Annika M. , Burden Andrea M. , Zellweger Urs , Tomka Ivan T. , Neuer Thomas , Roos Malgorzata , Kullak-Ublick Gerd A. , Curkovic Ivanka , Egbring Marco
Published: April 2020

Purpose

Heart failure is among the leading causes for hospitalization in Europe. In this study, we evaluate potential precipitating factors for hospitalization for heart failure and shock.

Methods

Using Swiss claims data (2014–2015), we evaluated the association between hospitalization for heart failure and shock, and prescription of oral potassium supplements, non-steroidal anti-inflammatory drugs (NSAIDs), and amoxicillin/clavulanic acid. We conducted case-crossover analyses, where exposure was compared for the hazard period and the primary control period (e.g., 1–30 days before hospitalization vs. 31–60 days, respectively). Conditional logistic regression was applied and subsequently adjusted for addressing potential confounding by disease progression. Sensitivity analyses were conducted and stratification for co-medication was performed.

Results

We identified 2185 patients hospitalized with heart failure or shock. Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid was significantly associated with an increased risk for hospitalization for heart failure and shock with crude odds ratios (OR) of 2.04 for potassium (95% CI 1.24–3.36, p = 0.005, 30 days), OR 1.8 for NSAIDs (95% CI 1.39–2.33, p < 0.0001, 30 days), and OR 3.25 for amoxicillin/clavulanic acid (95% CI 2.06–5.14, p < 0.0001, 15 days), respectively. Adjustment attenuated odds ratios, while the significant positive association remained (potassium OR 1.70 (95% CI 1.01–2.86, p = 0.046), NSAIDs OR 1.50 (95% CI 1.14–1.97, p = 0.003), and amoxicillin/clavulanic acid OR 2.26 (95% CI 1.41–3.62, p = 0.001).

Conclusion

Prescription of potassium supplements, NSAIDs, and amoxicillin/clavulanic acid is associated with increased risk for hospitalization. Underlying conditions such as pain, electrolyte imbalances, and infections are likely contributing risk factors. Physicians may use this knowledge to better identify patients at risk and adapt patient management.
Safety of intravenous iron isomaltoside for iron deficiency and iron deficiency anemia in pregnancy
Authors: Wesström Jan
Published: April 2020

Purpose

To evaluate the efficacy and safety for mother and child of using intravenous iron isomaltoside (IV-IIM) during pregnancy.

Methods

Using an appointment register, we retrospectively identified all pregnant women who received a single dose of 1000 or 1500 mg IV-IIM in the maternity ward of Falu Hospital and subsequently gave birth between August 6, 2013 and July 31, 2018. Women who received IV-IIM (case group) were individually matched with pregnant women who did not receive IV-IIM (control group) by delivery date, maternal age (± 2 years), and parity. Adverse drug reactions (ADRs), demographic characteristics, hemoglobin and s-ferritin counts, pregnancy and delivery complications, and infant data (APGAR score, pH at umbilical artery, birthweight, birth length, intrauterine growth restriction and neonatal ward admission). Data were obtained from electronic patient charts. SPSS was used for descriptive statistics.

Results

During the 5-year period, 213 women each received a single administration of IV-IIM. Ten (4.7%) ADRs occurred during IV-IIM administration. All ADRs were mild hypersensitivity reactions, abated spontaneously within a few minutes, and did not recur on rechallenge. No association between IIM dose and ADR frequency was noted. Maternal and fetal outcomes, including hemoglobin counts at delivery and postpartum, were similar in the case and control groups.

Conclusion

These results support the convenience, safety, and efficacy of a single high-dose (up to 1500 mg) infusion of IV-IIM for iron deficiency or iron deficiency anemia during pregnancy.
Facial nerve electrodiagnostics for patients with facial palsy: a clinical practice guideline
Authors: Guntinas-Lichius Orlando , Volk Gerd Fabian , Olsen Kerry D. , Mäkitie Antti A. , Silver Carl E. , Zafereo Mark E. , Rinaldo Alessandra , Randolph Gregory W. , Simo Ricard , Shaha Ashok R. , Vander Poorten Vincent , Ferlito Alfio
Published: April 2020

Purpose

Facial nerve electrodiagnostics is a well-established and important tool for decision making in patients with facial nerve diseases. Nevertheless, many otorhinolaryngologist—head and neck surgeons do not routinely use facial nerve electrodiagnostics. This may be due to a current lack of agreement on methodology, interpretation, validity, and clinical application. Electrophysiological analyses of the facial nerve and the mimic muscles can assist in diagnosis, assess the lesion severity, and aid in decision making. With acute facial palsy, it is a valuable tool for predicting recovery.

Methods

This paper presents a guideline prepared by members of the International Head and Neck Scientific Group and of the Multidisciplinary Salivary Gland Society for use in cases of peripheral facial nerve disorders based on a systematic literature search.

Results

Required equipment, practical implementation, and interpretation of the results of facial nerve electrodiagnostics are presented.

Conclusion

The aim of this guideline is to inform all involved parties (i.e. otorhinolaryngologist—head and neck surgeons and other medical specialists, therapeutic professionals and the affected persons) and to provide practical recommendations for the diagnostic use of facial nerve electrodiagnostics.
Fears from the past? The innate ability of dogs to detect predator scents
Authors: Samuel Lydia , Arnesen Charlotte , Zedrosser Andreas , Rosell Frank
Published: April 2020

Throughout the animal kingdom, antipredator mechanisms are an evolutionary driving force to enable the survival of species classified as prey. Information regarding a predator’s location can be determined through chemosensory cues from urine, faeces, visual and/or acoustic signals and anal gland secretions; and in several lab and field-based studies it has been seen that these cues mediate behavioural changes within prey species. These behaviours are often linked to fear and avoidance, which will in turn increase the prey’s survival rate. In many studies dogs (Canis lupus familiaris) have been used as a predator species, however, no research has addressed a dog’s innate ability to detect predator scents, hence the rationale behind this study. We assessed the innate ability of the untrained domestic dog to detect faecal scents of wild Eurasian brown bear (Ursus arctos arctos) and European lynx (Lynx lynx). The study monitored 82 domestic dogs across the UK and Norway. The dogs were exposed to the two predator faecal scents from Eurasian brown bear and European lynx, a herbivore faecal scent of Eurasian beaver (Castor fiber) and water control. Measurements were taken upon the time spent within a 40 cm radius of each scent and changes in the dog’s heart rate when within this 40 cm radius. We found dogs spent a decreased length of time around the predator scents and had an increased heart rate in relation to their basal heart rate. We conclude that dogs can innately sense predator scents of brown bear and lynx and elicit fear towards these odours, as shown through behavioural and physiological changes.
Is the UK Supreme Court rogue to un-prorogue Parliament?
Authors: Tridimas Constantina P. , Tridimas George
Published: April 2020

On 24 September 2019, in a unanimous judgment the UK Supreme Court ([2019] UKSC 41) ruled that the Prime Minister’s action to prorogue (suspend) Parliament for 5 weeks in the run-up to the 31-10-2019 deadline of the UK leaving the European Union, was unlawful and of no effect, as it prevented Parliament from carrying out its constitutional functions without reasonable justification. Although the Court did not pronounce on the merits and demerits of Brexit, its decision delighted “Remainers” but appalled “Leavers”. The Court ruling epitomises the potency of constitutional review by an independent judiciary. The paper applies collective choice theory to analyse the ruling of the Supreme Court. This is accomplished by (a) examining the legal basis of the Court ruling; (b) reviewing arguments for judicial review and (c) exploring the effect of the Court as an additional player in the game of collective choice in a spatial decision model.
Prediction of geometry deviations in additive manufactured parts: comparison of linear regression with machine learning algorithms
Authors: Baturynska Ivanna , Martinsen Kristian
Published: April 2020

Dimensional accuracy in additive manufacturing (AM) is still an issue compared with the tolerances for injection molding. In order to make AM suitable for the medical, aerospace, and automotive industries, geometry variations should be controlled and managed with a tight tolerance range. In the previously published article, the authors used statistical analysis to develop linear models for the prediction of dimensional features of laser-sintered specimens. Two identical builds with the same material, process, and build parameters were produced, resulting in 434 samples for mechanical testing (ISO 527-2 1BA). The developed linear models had low accuracy, and therefore needed an application of more advanced data analysis techniques. In this work, machine learning techniques are applied for the same data, and results are compared with the previously reported linear models. The linear regression model is the best for width. Multilayer perceptron and gradient boost regressor models have outperformed other for thickness and length. The recommendations on how the developed models can be used in the future are proposed.
Cassava shrunken-2 homolog MeAPL3 determines storage root starch and dry matter content and modulates storage root postharvest physiological deterioration
Authors: Beyene Getu , Chauhan Raj Deepika , Gehan Jackson , Siritunga Dimuth , Taylor Nigel
Published: April 2020

Key message

Among the five cassava isoforms (MeAPL1–MeAPL5), MeAPL3 is responsible for determining storage root starch content. Degree of storage root postharvest physiological deterioration (PPD) is directly correlated with starch content.

AGPase is heterotetramer composed of two small and two large subunits each coded by small gene families in higher plants. Studies in cassava (Manihot esculenta) identified and characterized five isoforms of Manihot esculenta ADP-glucose pyrophosphorylase large subunit (MeAPL1–MeAPL5) and employed virus induced gene silencing (VIGS) to show that MeAPL3 is the key isoform responsible for starch and dry matter accumulation in cassava storage roots. Silencing of MeAPL3 in cassava through stable transgenic lines resulted in plants displaying significant reduction in storage root starch and dry matter content (DMC) and induced a distinct phenotype associated with increased petiole/stem angle, resulting in a droopy leaf phenotype. Plants with reduced starch and DMC also displayed significantly reduced or no postharvest physiological deterioration (PPD) compared to controls and lines with high DMC and starch content. This provides strong evidence for direct relationships between starch/dry matter content and its role in PPD and canopy architecture traits in cassava.
Another look at value and momentum: volatility spillovers
Authors: Grobys Klaus , Vähämaa Sami
Published: April 2020

This paper examines volatility interdependencies between value and momentum returns. Using U.S. data over the period 1926–2015, we document persistent periods of low and high volatility spillovers between value and momentum strategies. Moreover, we find that the intensity of the volatility spillovers may change substantially in very short periods of time and that these shifts in spillover intensity can be linked to prominent economic events and financial market turmoil. Our results further demonstrate that value returns increase and momentum returns decrease monotonically with increasing volatility spillovers between the two strategies. Given this linkage between spillover intensity and returns, we propose a simple trading strategy which utilizes a volatility spillover index for allocating funds between value and momentum portfolios. The proposed trading strategy outperforms value and momentum strategies and generates payoffs that are not subject to option-like behavior.
Needs and cost-effectiveness in health care priority setting
Authors: Gustavsson Erik , Tinghög Gustav
Published: April 2020

How to balance the maximization of health and concerns for the worse off remains a challenge for health care decision makers when setting priorities. In regulatory guidelines these concerns are typically specified in terms of priority setting according to needs and priority setting according to cost-effectiveness. Still, it is often unclear when and why needs and cost-effectiveness diverge or overlap as guiding priority setting principles in practice. We conduct a comparative analysis of need and cost-effectiveness in the context of health care priority setting. Based on theories of distributive justice we specify three normative interpretations of need and explicate how these relate to the normative basis for cost-effectiveness analysis. Using priority-setting dilemmas we then move on to explicate when and why need and cost-effectiveness diverge as priority-setting principles. We find that: (i) although principles of need and cost-effectiveness may recommend the same allocation of resources the underlying reason for an allocation is different; (ii) while they both may give weight to patients who are worse off they do so in different ways and to different degree; and (iii) whereas cost-effectiveness clearly implies the aggregation of benefits across individuals principles of needs give no guidance with regard to if, and if so, how needs should be aggregated. Priority setting according to needs or cost-effectiveness does not necessarily recommend different allocations of resources. Thus, the normative conflict between them, often highlighted in practice, seems exaggerated. For health policy this is important knowledge because unclear conceptions may obstruct an informed public discussion. Moreover, if decision-makers are to properly account for both principles they need to recognize the inconsistencies as well as similarities between the two.
Measuring happiness increases happiness
Authors: Roessler Jannik , Gloor Peter A.
Published: April 2020

Happiness has been an overarching goal of mankind at least since Aristotle spoke of Eudaimonia. However measuring happiness has been elusive and until now has almost exclusively been done by asking survey questions about self-perceived happiness. We propose a novel approach, tracking happiness and stress through changes in body signals with a smartwatch, the “Happimeter”. It predicts individual emotions from sensor data collected by an Android Wear smartwatch, such as acceleration, heartbeat, and activity. The Happimeter was used over three months in the innovation lab of a bank with 22 employees to measure individual happiness, activity, and stress. The participants were randomly divided into an experimental and a control group of similar size. Both groups wore the watch and entered their subjective happiness, activity and stress levels several times a day. The user-entered ratings were then used to train a machine learning system using the sensors of the smartwatch to subsequently automatically predict happiness, activity, and stress. The experimental group received ongoing feedback about their mood and which activity, sensor signals, or other people, made them happier or unhappier, while the control group did not get any feedback about their predicted and manually entered emotions. Just like in quantum physics we observed a “Heisenberg Effect”, where the participants made aware of their measurements changed their behavior: Members of the experimental group that received happiness feedback were 16% happier, and 26% more active than the control group at the end of the experiment. No effect was observed for stress.
ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738
Authors: Jette Nicholas R. , Radhamani Suraj , Ye Ruiqiong , Yu Yaping , Arthur Greydon , Goutam Siddhartha , Bismar Tarek A. , Kumar Mehul , Bose Pinaki , Yip Steven , Kolinsky Michael , Lees-Miller Susan P.
Published: April 2020

The Ataxia Telangiectasia Mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP-ribose polymerase (PARP) inhibitor olaparib induces transient G2 arrest but not cell death in ATM-deficient lung cancer cells, while the combination of olaparib with the ATM- and Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that combination of olaparib plus the clinically relevant ATR inhibitor AZD6738 also induces cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. Together, our data suggest that lung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.
The pope’s man in London: Anglo-Vatican relations, the nuncio question and Irish concerns, 1938-82
Authors: Corráin Daithí Ó
Published: April 2020

Although a British mission to the Holy See was established in 1914, the diplomatic relationship was not on a basis of reciprocity. From 1938 the pope was represented in London not by a nuncio (the Vatican equivalent of an ambassador) but by an apostolic delegate whose mission was to the hierarchy alone and not the British government. The evolution of the nuncio question sheds light on the nature of Anglo-Vatican relations, the place of Catholicism in British public life, inter-church rapprochement and British foreign policy considerations. This article assesses the divergent positions of the Foreign and Home Offices. The former was sympathetic to a change of status, whereas the latter was cautious due to the opposition of the archbishop of Canterbury and concerns about anti-Catholicism. The nuncio question was also of great interest to the Irish government. It feared that a nuncio in London would exert jurisdiction over Northern Ireland and undermine the all-island unity of the Irish Catholic Church. The Northern Ireland Troubles and the support displayed by the apostolic delegate for British policy hastened the restoration of full ambassadorial relations between London and the Holy See in 1982, ending a diplomatic breach that had existed for more than four centuries. It paved the way for Pope John Paul II’s historic pastoral visit to Britain which helped to consolidate the position of Roman Catholicism in British national life.
The Action for Damages as a Fundamental Rights Remedy: Holding Frontex Liable
Authors: Fink Melanie
Published: April 2020

Frontex has become one of the major players in European external border management. As its powers and resources have increased, so have the challenges surrounding its compliance with fundamental rights. A major concern continues to be how to ensure legal accountability for fundamental rights violations that occur in the context of its activities. While Member States can be held accountable before their own national courts and before international courts, neither of these options are available in relation to Frontex. But it can be brought before the Court of Justice of the European Union to account for the conformity of its conduct with EU law. This Article explores the potential of the EU action for damages to offer a remedy for fundamental rights violations committed by Frontex. It identifies where public liability law falls short of providing a remedy for fundamental rights violations committed by EU bodies, explores the possibilities to close that gap, and assesses the implications this has for Frontex’s liability. The Article argues that the action for damages may be the means to close the accountability gap in the specific case of Frontex, but also more generally in circumstances where EU administration is delivered in the form of informal or factual conduct. If it is to fulfill that role, the CJEU would have to lower the threshold for EU liability where fundamental rights are concerned.
Holding the European Asylum Support Office Accountable for its role in Asylum Decision-Making: Mission Impossible?
Authors: Tsourdi Evangelia (Lilian)
Published: April 2020

The Common European Asylum System (CEAS) seeks to harmonize national asylum procedures. The initial implementation design of the CEAS, reflective of the theory of executive federalism, foresaw that national authorities were to conduct asylum processing and implement the harmonized norms. The implementation design of the EU asylum policy has, nevertheless, started to shift. An integrated European administration is emerging. One area this is pronounced in is asylum decision-making, where patterns of joint implementation have surfaced. This term broadly refers to staff and experts deployed by the European Asylum Support Office (EASO), an EU agency, working alongside national administrators, including on the processing of asylum claims. This Article scrutinizes the emergence of joint implementation patterns in EU asylum policy and the resulting accountability challenge, drawing both from legal analysis and political science theories. I also refer to administrative practice as documented in secondary sources. EASO is currently subject to a mosaic of accountability processes. Two main pitfalls emerge: the intricate balance between accountability and independence; and accessibility for the individual. Against this backdrop, I focus on extra-judicial accountability through the European Ombudsman which, combined with the envisaged internal “individual complaints mechanism” within EASO, could go some way in ensuring applicants’ procedural rights.
On the relaxation of integral functionals depending on the symmetrized gradient
Authors: Kosiba Kamil , Rindler Filip
Published: April 2020

We prove results on the relaxation and weak* lower semicontinuity of integral functionals of the form$${\cal F}[u]: = \int_\Omega f \left( {\displaystyle{1 \over 2}\left( {\nabla u(x) + \nabla u{(x)}^T} \right)} \right) \,{\rm d}x,\quad u:\Omega \subset {\mathbb R}^d\to {\mathbb R}^d,$$over the space BD(Ω) of functions of bounded deformation or over the Temam–Strang space$${\rm U}(\Omega ): = \left\{ {u\in {\rm BD}(\Omega ):\;\,{\rm div}\,u\in {\rm L}^2(\Omega )} \right\},$$depending on the growth and shape of the integrandf. Such functionals are interesting, for example, in the study of Hencky plasticity and related models.
STEPPED-COMBUSTION14C DATING IN LOESS-PALEOSOL SEDIMENT
Authors: Cheng Peng , Fu Yunchong
Published: April 2020

In this study, low temperature (room temperature, 400°C LT) and high temperature (400–900°C HT) of bulk organic carbon samples were dated from two loess and paleosol profiles. The results showed that radiocarbon (14C) dates of the LT were younger than HT fractions, indicating effect of younger contamination from overlying layers. The δ13C variation of the HT fraction appears to respond much more sensitively to climate change, and14C ages of HT fraction can produce reasonable14C ages from a younger layer, but it is very difficult to obtain reliable14C ages from older layer as a result of uncomplete removal of young carbon.
Landslide Disparities, Flume Discoveries, and Oso Despair
Authors: Iverson Richard M.
Published: April 2020

Landslide dynamics is the branch of science that seeks to understand the motion of landslides by applying Newton's laws. This memoir focusses on a 40‐year effort to understand motion of highly mobile—and highly lethal—landslides such as debris avalanches and debris flows. A major component of this work entailed development and operation of the U.S. Geological Survey debris flow flume, a unique, large‐scale experimental facility in Oregon. Experiments there yielded new insights that informed development of mathematical models that were aimed not only at explaining landslide dynamics but also at evaluating landslide and debris flow hazards. The most sophisticated of these models, called D‐Claw, found its first practical application during investigations of the 2014 Oso, Washington, landslide disaster. That event provided indelible lessons about the utility and sociology of science in the real world.
Molecular Characterization of Organosulfates in Highly Polluted Atmosphere Using Ultra‐High‐Resolution Mass Spectrometry
Authors: Cai Dongmei , Wang Xinke , Chen Jianmin , Li Xiang
Published: April 2020

Organosulfates (OSs) have recently been observed to be a potentially important constituent of secondary organic aerosol (SOA); however, their molecular characterization in highly polluted atmospheres has not been probed in detail. This study thoroughly presents the characterization of OSs in polluted air and demonstrates their seasonal and diurnal variations, formation mechanisms, and contributions to organic aerosol. Atmospheric PM2.5 samples were collected from an urban Shanghai site across the winter and summer of 2017. OSs were characterized by ultra‐high‐performance liquid chromatography (UHPLC) coupled with Orbitrap mass spectrometry (MS). Based on exact mass formulae in conjunction with previous chamber studies, hundreds of sulfur‐containing compounds were tentatively identified as OSs. The number and abundance of OSs increased significantly during pollution episodes. The OSs in the clean aerosol samples were dominant in biogenic products, whereas the OSs in the polluted winter samples had distinctive anthropogenic characteristics. Aromatics and long‐chain alkanes from anthropogenic emissions might be their precursors. By using synthesized standards, the total concentrations of 14 quantified OSs ranged 21.6–161 ng m−3 in summer and 5.85–84.3 ng m−3 in winter, respectively. Among these OSs, glycolic acid sulfate was the most abundant species (1.13–122 ng m−3). Further analysis of their seasonal and diurnal variations suggests possible contributions from multiple formation mechanisms, including acid‐catalyzed and NO3‐initiated oxidation reactions. Our results highlight that increased anthropogenic pollutant emissions (e.g., NOx and SO2) can significantly enhance the SOA burden in biogenically influenced urban areas.
Zinc finger protein 703 induces EMT and sorafenib resistance in hepatocellular carcinoma by transactivating CLDN4 expression
Authors: Wang Hao , Xu Hongfa , Ma Feng , Zhan Meixiao , Yang Xiangyu , Hua Shengni , Li Wei , Li Yong , Lu Ligong
Published: April 2020

Metastasis is one of the most common reasons of hepatocellular carcinoma (HCC) death; however, the molecular mechanism underlying HCC metastasis remains incompletely defined. Here we report a new function of Zinc Finger Protein 703 (ZNF703), a member of the NET/NlZ family of zinc finger transcription factors, in promoting hepatocellular carcinoma metastasis. We demonstrated that the overexpression of ZNF703 in human HCC tissue is correlated with tumor metastasis and recurrence, it is also related with the prognosis and survival rate of patients. ZNF703 overexpression promotes HCC progression in vitro and in vivo, whereas ZNF703 knockdown has the opposite effect. In addition, ZNF703 induces epithelialmesenchymal transition (EMT) via directly binding to the CLDN4 promoter and transactivating CLDN4 expression. Downregulation of CLDN4 can attenuate ZNF703-mediated HCC metastasis, whereas upregulation of CLDN4 can reverse the decreased metastasis induced by ZNF703 knockdown. Our data revealed that ZNF703 expression is correlated with CLDN4 level, the overexpression of both ZNF703 and CLDN4 are leaded to poorer prognosis of patients with HCC. Moreover, ZNF703 knockdown can enhance the sensitivity of HCC cell to sorafenib, whereas ZNF703 overexpression has the opposite effect. These results suggested that ZNF703 might be a potential target for cancer therapies and a candidate prognostic biomarker for predicting whether patients with HCC are befitting for sorafenib treatment.
Mechanical cleaning of graphene using in situ electron microscopy
Authors: Schweizer Peter , Dolle Christian , Dasler Daniela , Abellán Gonzalo , Hauke Frank , Hirsch Andreas , Spiecker Erdmann
Published: April 2020

Avoiding and removing surface contamination is a crucial task when handling specimens in any scientific experiment. This is especially true for two-dimensional materials such as graphene, which are extraordinarily affected by contamination due to their large surface area. While many efforts have been made to reduce and remove contamination from such surfaces, the issue is far from resolved. Here we report on an in situ mechanical cleaning method that enables the site-specific removal of contamination from both sides of two dimensional membranes down to atomic-scale cleanliness. Further, mechanisms of re-contamination are discussed, finding surface-diffusion to be the major factor for contamination in electron microscopy. Finally the targeted, electron-beam assisted synthesis of a nanocrystalline graphene layer by supplying a precursor molecule to cleaned areas is demonstrated.
Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans
Authors: Wei Wei , Pagnamenta Alistair T. , Gleadall Nicholas , Sanchis-Juan Alba , Stephens Jonathan , Broxholme John , Tuna Salih , Odhams Christopher A. ,   Genomics England Research Consortium, Ambrose J. C. , Baple E. L. , Bleda M. , Boardman-Pretty F. , Boissiere J. M. , Boustred C. R. , Caulfield M. J. , Chan G. C. , Craig C. E. H. , Daugherty L. C. , de Burca A. , Devereau A. , Elgar G. , Foulger R. E. , Fowler T. , Furió-Tarí P. , Hackett J. M. , Halai D. , Holman J. E. , Hubbard T. J. P. , Jackson R. , Kasperaviciute D. , Kayikci M. , Lahnstein L. , Lawson K. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , Mason J. , McDonagh E. M. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , Odhams C. A. , Patch C. , Perez-Gil D. , Polychronopoulos D. , Pullinger J. , Rahim T. , Rendon A. , Riesgo-Ferreiro P. , Rogers T. , Ryten M. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smedley D. , Smith K. R. , Sosinsky A. , Spooner W. , Stevens H. E. , Stuckey A. , Sultana R. , Thomas E. R. A. , Thompson S. R. , Tregidgo C. , Tucci A. , Walsh E. , Watters S. A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. ,   NIHR BioResource, Sanchis-Juan Alba , Stephens Jonathan , Tuna Salih , Turro Ernest , Chinnery Patrick F. , Fratter Carl , Turro Ernest , Caulfield Mark J. , Taylor Jenny C. , Rahman Shamima , Chinnery Patrick F.
Published: April 2020

Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored a ‘heteroplasmic haplotype’ consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5–25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.
Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation
Authors: Laurien Lucie , Nagata Masahiro , Schünke Hannah , Delanghe Tom , Wiederstein Janica L. , Kumari Snehlata , Schwarzer Robin , Corona Teresa , Krüger Marcus , Bertrand Mathieu J. M. , Kondylis Vangelis , Pasparakis Manolis
Published: April 2020

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.
Developing a new class of engineered live bacterial therapeutics to treat human diseases
Authors: Charbonneau Mark R. , Isabella Vincent M. , Li Ning , Kurtz Caroline B.
Published: April 2020

A complex interplay of metabolic and immunological mechanisms underlies many diseases that represent a substantial unmet medical need. There is an increasing appreciation of the role microbes play in human health and disease, and evidence is accumulating that a new class of live biotherapeutics comprised of engineered microbes could address specific mechanisms of disease. Using the tools of synthetic biology, nonpathogenic bacteria can be designed to sense and respond to environmental signals in order to consume harmful compounds and deliver therapeutic effectors. In this perspective, we describe considerations for the design and development of engineered live biotherapeutics to achieve regulatory and patient acceptance.
A general 11C-labeling approach enabled by fluoride-mediated desilylation of organosilanes
Authors: Qu Wenchao , Hu Bao , Babich John W. , Waterhouse Nicole , Dooley Marybeth , Ponnala Shashikanth , Urgiles Julie
Published: April 2020

Carbon-11 (11C) is one of the most ideal positron emitters for labeling bioactive molecules for molecular imaging studies. The lack of convenient and fast incorporation methods to introduce 11C into organic molecules often hampers the use of this radioisotope. Here, a fluoride-mediated desilylation (FMDS) 11C-labeling approach is reported. This method relies on thermodynamically favored Si-F bond formation to generate a carbanion, therefore enabling the highly efficient and speedy incorporation of [11C]CO2 and [11C]CH3I into molecules with diversified structures. It provides facile and rapid access to 11C-labeled compounds with carbon-11 attached at various hybridized carbons as well as oxygen, sulfur and nitrogen atoms with broad functional group tolerance. The exemplified syntheses of several biologically and clinically important radiotracers illustrates the potentials of this methodology.
Author Correction: Diagnosis of fusion genes using targeted RNA sequencing
Authors: Heyer Erin E. , Deveson Ira W. , Wooi Danson , Selinger Christina I. , Lyons Ruth J. , Hayes Vanessa M. , O’Toole Sandra A. , Ballinger Mandy L. , Gill Devinder , Thomas David M. , Mercer Tim R. , Blackburn James
Published: April 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Lipid moieties of Mycoplasma pneumoniae lipoproteins are the causative factor of vaccine-enhanced disease
Authors: Mara Arlind B. , Gavitt Tyler D. , Tulman Edan R. , Geary Steven J. , Szczepanek Steven M.
Published: April 2020

Vaccine-enhanced disease (VED) occurs as a result of vaccination followed by infection with virulent Mycoplasma pneumoniae. To date VED has prevented development of an efficacious vaccine against this significant human respiratory pathogen. Herein we report that vaccination of BALB/c mice with M. pneumoniae lipid-associated membrane proteins (LAMPs) induces lung lesions consistent with exacerbated disease following challenge, without reducing bacterial loads. Removal of lipid moieties from LAMPs prior to vaccination eliminates VED and reduces bacterial loads after infection. Collectively, these data indicate that lipid moieties of lipoproteins are the causative factors of M. pneumoniae VED.
Probabilistic modeling to estimate jellyfish ecophysiological properties and size distributions
Authors: Ramondenc Simon , Eveillard Damien , Guidi Lionel , Lombard Fabien , Delahaye Benoît
Published: April 2020

While Ocean modeling has made significant advances over the last decade, its complex biological component is still oversimplified. In particular, modeling organisms in the ocean system must integrate parameters to fit both physiological and ecological behaviors that are together very difficult to determine. Such difficulty occurs for modeling Pelagia noctiluca. This jellyfish has a high abundance in the Mediterranean Sea and could contribute to several biogeochemical processes. However, gelatinous zooplanktons remain poorly represented in biogeochemical models because uncertainties about their ecophysiology limit our understanding of their potential role and impact. To overcome this issue, we propose, for the first time, the use of the Statistical Model Checking Engine (SMCE), a probability-based computational framework that considers a set of parameters as a whole. Contrary to standard parameter inference techniques, SMCE identifies sets of parameters that fit both laboratory-culturing observations and in situ patterns while considering uncertainties. Doing so, we estimated the best parameter sets of the ecophysiological model that represents the jellyfish growth and degrowth in laboratory conditions as well as its size. Behind this application, SMCE remains a computational framework that supports the projection of a model with uncertainties in broader contexts such as biogeochemical processes to drive future studies.
Uncovering spatial and ecological variability in gap size frequency distributions in the Canadian boreal forest
Authors: Goodbody Tristan R. H. , Tompalski Piotr , Coops Nicholas C. , White Joanne C. , Wulder Michael A. , Sanelli Marco
Published: April 2020

Analyses characterizing canopy gaps are required to improve our understanding of spatial and structural variations in forest canopies and provide insight into ecosystem-level successional processes. Gap size frequency distributions (GSFD) are indicative of ecological processes and disturbance patterns. To date, GSFD in boreal forest ecosystems have not been systematically quantified over large areas using a single consistent data source. Herein we characterized GSFDs across the entirety of the Canadian boreal forest using transects of airborne laser scanning (ALS) data. ALS transects were representatively sampled within eight distinct Canadian boreal ecozones. Gaps were detected and delineated from the ALS-derived canopy height model as contiguous canopy openings ≥8 m2with canopy heights ≤3 m. Gaps were then stratified by ecozone and forest type (i.e. coniferous, broadleaf, mixedwood, wetland-treed), and combinations thereof, and GSFDs were calculated for each stratum. GSFDs were characterized by the scaling parameter of the power-law probability distribution, lambda (λ) and Kolmogorov-Smirnov tests confirmed that GSFDs for each stratum followed a power-law distribution. Pairwise comparisons between ecozones, forest types, and combinations thereof indicated significant differences between estimates of λ. Scaling parameters were found to be more variable by ecozone (1.96–2.31) than by forest type (2.15–2.21). These results contrast those of similar studies done in tropical forest environments, whereby λ was found to be relatively consistent across a range of site types, geological substrates, and forest types. The geographic range considered herein is much larger than that of previous studies, and broad-scale patterns in climate, landforms, and soils that are reflected in the definition of unique ecozones, likely also influence gap characteristics.
Apatinib Monotherapy for Chemotherapy-Refractory Metastatic Colorectal Cancer: A Multi-centre, Single-Arm, Prospective Study
Authors: Wang Fen , Yuan Xia , Jia Jun , Bi Xiaoxia , Zhou Zeqiang , Zhou Qiming , Li Xia , Luo Changguo , Deng Minghui , Yi Liangjie , Li Yong , Lu Jianxin , Su Wenzhi , Chen Hanbin , Zhu Yu , Wang Shubin
Published: April 2020

Angiogenesis inhibitors are of considerable interest for treating metastatic colorectal cancer (mCRC). This trial evaluated the efficacy and safety of apatinib in chemotherapy-refractory mCRC. Apatinib 500 mg was administered daily to patients who had progressed after two or more lines of standard fluorouracil-based chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Overall, 48 patients were enrolled. ORR and DCR were 8.3% (4/48) and 68.8% (33/48), respectively. Median PFS and OS were 4.8 (95% confidence interval [CI], 3.653–5.887) and 9.1 months (95% CI, 5.155–13.045), respectively, and did not differ between subgroups stratified by previous anti-angiogenic therapies. The most prevalent grade 3–4 adverse events were hypertension (12.5%), hand-foot syndrome (HFS, 10.4%), thrombocytopenia (10.4%), and proteinuria (8.3%). Low baseline neutrophil/lymphocyte ratio (NLR, hazard ratios [HR], 0.619; P = 0.027), early carbohydrate antigen 19–9 (CA19–9) decrease (HR, 1.654; P = 0.016), and HFS (HR, 2.087; P = 0.007) were associated with improved PFS. In conclusion, apatinib monotherapy demonstrated encouraging efficacy with manageable toxicities in chemotherapy-refractory mCRC. Previous anti-angiogenic therapies did not influence outcomes. Baseline NLR, early CA19-9 decrease, and HFS could predict the efficacy of apatinib.
Parity is associated with cognitive function and brain age in both females and males
Authors: Ning Kaida , Zhao Lu , Franklin Meredith , Matloff Will , Batta Ishaan , Arzouni Nibal , Sun Fengzhu , Toga Arthur W.
Published: April 2020

Previous studies of the association between parity and long-term cognitive changes have primarily focused on women and have shown conflicting results. We investigated this association by analyzing data collected on 303,196 subjects from the UK Biobank. We found that in both females and males, having offspring was associated with a faster response time and fewer mistakes made in the visual memory task. Subjects with two or three children had the largest differences relative to those who were childless, with greater effects observed in men. We further analyzed the association between parity and relative brain age (n = 13,584), a brain image-based biomarker indicating how old one’s brain structure appears relative to peers. We found that in both sexes, subjects with two or three offspring had significantly reduced brain age compared to those without offspring, corroborating our cognitive function results. Our findings suggest that lifestyle factors accompanying having offspring, rather than the physical process of pregnancy experienced only by females, contribute to these associations and underscore the importance of studying such factors, particularly in the context of sex.
Hierarchical clustering of MS/MS spectra from the firefly metabolome identifies new lucibufagin compounds
Authors: Rawlinson Catherine , Jones Darcy , Rakshit Suman , Meka Shiv , Moffat Caroline S. , Moolhuijzen Paula
Published: April 2020

Metabolite identification is the greatest challenge when analysing metabolomics data, as only a small proportion of metabolite reference standards exist. Clustering MS/MS spectra is a common method to identify similar compounds, however interrogation of underlying signature fragmentation patterns within clusters can be problematic. Previously published high-resolution LC-MS/MS data from the bioluminescent beetle (Photinus pyralis) provided an opportunity to mine new specialized metabolites in the lucibufagin class, compounds important for defense against predation. We aimed to 1) provide a workflow for hierarchically clustering MS/MS spectra for metabolomics data enabling users to cluster, visualise and easily interrogate the identification of underlying cluster ion profiles, and 2) use the workflow to identify key fragmentation patterns for lucibufagins in the hemolymph of P. pyralis. Features were aligned to their respective MS/MS spectra, then product ions were dynamically binned and resulting spectra were hierarchically clustered and grouped based on a cutoff distance threshold. Using the simplified visualization and the interrogation of cluster ion tables the number of lucibufagins was expanded from 17 to a total of 29.
De novo sensitization during subcutaneous allergen specific immunotherapy - an analysis of 51 cases of SCIT and 33 symptomatically treated controls
Authors: Gellrich Donata , Eder Katharina , Högerle Catalina , Becker Sven , Canis Martin , Gröger Moritz
Published: April 2020

Since the beneficial implementation of allergen specific subcutaneous immunotherapy (SCIT), there are only a few studies on the risk of SCIT-induced neosensitizations. In 51 patients, we retrospectively analyzed sIgE and sIgG patterns by a multiplex ELISA as well as demographic and clinical features before and after SCIT. 33 allergic patients, who only received symptomatic treatment, served as controls. In 12 of 51 SCIT-treated patients (24%), we found new sIgE against allergen components of the allergen source treated by SCIT; eight of them were adults. Among controls, no adult patient showed neosensitization to components of the primarily affected allergen source. Only two children of the control group were affected by neosensitization, which was limited to major allergen components and rarely accompanied by sIgG. In the SCIT-treated group, neosensitization affected major and minor allergen components, and was accompanied by a strong induction of sIgG against major components. A clear clinical predictor of neosensitization during SCIT was not found. Comparing symptom scores, patients seem to profit more from SCIT, if neosensitization remained absent. Patients undergoing SCIT might carry an enhanced risk of neosensitization towards formerly unrecognized allergen components. According to anamnestic data, these neosensitizations might be of clinical relevance - supporting attempts towards personalized recombinant vaccines.
Association between serum uric acid levels and mortality: a nationwide community-based cohort study
Authors: Konta Tsuneo , Ichikawa Kazunobu , Kawasaki Ryo , Fujimoto Shouichi , Iseki Kunitoshi , Moriyama Toshiki , Yamagata Kunihiro , Tsuruya Kazuhiko , Narita Ichiei , Kondo Masahide , Shibagaki Yugo , Kasahara Masato , Asahi Koichi , Watanabe Tsuyoshi
Published: April 2020

Hyperuricemia is associated with all-cause and cardiovascular mortality. However, the threshold value of serum uric acid levels for increased risk of mortality has not been determined. This large-scale cohort study used a nationwide database of 500,511 Japanese subjects (40–74 years) who participated in the annual health checkup and were followed up for 7 years. The association of serum uric acid levels at baseline with cardiovascular and all-cause mortality was examined. The Cox proportional hazard model analysis with adjustment for possible confounders revealed that the all-cause and cardiovascular mortality showed a J-shaped association with serum uric acid levels at baseline in both men and women. A significant increase in the hazard ratio for all-cause mortality was noted with serum uric acid levels ≥ 7 mg/dL in men and ≥ 5 mg/dL in women. A similar trend was observed for cardiovascular mortality. This study disclosed that even a slight increase in serum uric acid levels was an independent risk factor for all-cause and cardiovascular mortality in both men and women in a community-based population. Moreover, the threshold values of uric acid for mortality might be different for men and women.