bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive proof-search for equational reasoning
Authors: Miranda-Perea Favio E , González Huesca Lourdes del Carmen , Linares-Arévalo P Selene
Published: March 2020

Equational reasoning arises in many areas of mathematics and computer science. It is a cornerstone of algebraic reasoning and results essential in tasks of specification and verification in functional programming, where a program is mainly a set of equations. The usual manipulation of identities while conducting informal proofs obviates many intermediate steps that are neccesary while developing them using a formal system, such as the equationally complete Birkhoff calculus ${\mathcal{B}}$. This deductive system does not fit in the common manner of doing mathematical proofs, and it is not compatible with the mechanisms of proof assistants. The aim of this work is to provide a deductive system ${\mathcal{B}}^{\textrm{GOAL}}$ for equality, equivalent to ${\mathcal{B}}$ but suitable for constructing equational proofs in a backward fashion. This feature makes it adequate for interactive proof-search in the approach of proof assistants. This will be achieved by turning ${\mathcal{B}}^{\textrm{GOAL}}$ into a transition system of formal tactics in the style of Edinburgh LCF, such transformation allows us to give a direct formal definition of backward proof in equational logic.
Nelson’s logic 𝒮
Authors: Nascimento Thiago , Rivieccio Umberto , Marcos João , Spinks Matthew
Published: March 2020

Besides the better-known Nelson logic ($\mathcal{N}3$) and paraconsistent Nelson logic ($\mathcal{N}4$), in 1959 David Nelson introduced, with motivations of realizability and constructibility, a logic called $\mathcal{S}$. The logic $\mathcal{S}$ was originally presented by means of a calculus (crucially lacking the contraction rule) with infinitely many rule schemata and no semantics (other than the intended interpretation into Arithmetic). We look here at the propositional fragment of $\mathcal{S}$, showing that it is algebraizable (in fact, implicative), in the sense of Blok and Pigozzi, with respect to a variety of three-potent involutive residuated lattices. We thus introduce the first known algebraic semantics for $\mathcal{S}$ as well as a finite Hilbert-style calculus equivalent to Nelson’s presentation; this also allows us to clarify the relation between $\mathcal{S}$ and the other two Nelson logics $\mathcal{N}3$ and $\mathcal{N}4$.
A nationwide survey of fatigue in cancer patients in Taiwan: an unmet need
Authors: Rau Kun-Ming , Shun Shiow-Ching , Chiou Tzeon-Jye , Lu Chang-Hsien , Ko Wei-Hsu , Lee Ming-Yang , Huang Wen-Tsung , Yeh Kun-Huei , Chang Cheng-Shyong , Hsieh Ruey-Kuen
Published: March 2020

Background

Cancer-related fatigue (CRF) is an emerging clinical issue, although its prevalence and impact on quality of life (QOL) in cancer patients in Taiwan remain unclear. The present nationwide cross-sectional study was conducted to provide a thorough overview of the prevalence, related factors and impact of CRF in Taiwan.

Methods

In this multi-center survey, data were collected using the International Classification of Diseases 10th Revision (ICD-10) Fatigue evaluation, Brief Fatigue Inventory–Taiwan (BFI-T), the Chinese version of the Symptom Distressed Scale and a fatigue experience survey. Logistic regression was used to determine the correlations between fatigue characteristics and the factors studied.

Results

A total of 1207 cancer patients were recruited from 23 hospitals in Taiwan. Fatigue was the most distressing symptom in Taiwanese cancer patients. The distress score was higher if CRF was diagnosed using ICD-10 compared with BFI-T. Rest and nutritional supplementation were the most common non-pharmacological treatments; blood transfusion was the most common pharmacological treatment. There were 45% of patients reported not receiving a timely intervention for fatigue.

Conclusions

Fatigue is the most bothersome symptom reported by Taiwanese cancer patients. Caregivers should be aware of the impact of CRF on QOL in cancer patients, constantly measure the severity of fatigue and provide appropriate interventions.
DISPENSING WITH INDISPENSABILITY
Authors: Dunne Niamh
Published: March 2020

‘Indispensability’ is the central concept underpinning the treatment of refusal to deal claims under Article 102 TFEU. Since its adoption in Magill and Bronner, however, the conventional wisdom that instances of refusal to deal constitute an abuse only in the presence of indispensability has been challenged from multiple directions. This article surveys the departures from the orthodoxy that can be found in the jurisprudence. In doing so, it measures the purported explanations for such derogations against the justifications for restraint encapsulated in the indispensability concept. Finally, it asks whether the weight of exceptions may reach the point of overwhelming, or ‘dispensing with,’ the original rule.
AtHSPR is involved in GA- and light intensity-mediated control of flowering time and seed set in Arabidopsis
Authors: Yang Tao , Sun Yan , Wang Yongli , Zhou Lina , Chen Mengya , Bian Zhiyuan , Lian Yuke , Xuan Lijuan , Yuan Guoqiang , Wang Xinyu , Wang Chongying
Published: March 2020

Flowering is a dynamic and synchronized process, the timing of which is finely tuned by various environmental signals. A T-DNA insertion mutant in Arabidopsis HEAT SHOCK PROTEIN-RELATED (AtHSPR) exhibited late-flowering phenotypes under both long-day (LD) and short-day (SD) conditions compared to the wild-type, while over-expression of AtHSPR promoted flowering. Exogenous application of gibberellin (GA) partially rescued the late-flowering mutant phenotype under both LD and SD conditions, suggesting that AtHSPR is involved in GA biosynthesis and/or the GA signaling that promotes flowering. Under SD or low-light conditions, the Athspr mutant exhibited late flowering together with reduced pollen viability and seed set, defective phenotypes that were partially rescued by GA treatment. qRT-PCR assays confirmed that GA biosynthetic genes were down-regulated, that GA catabolic genes were up-regulated, and that the levels of bioactive GA and its intermediates were decreased in Athspr under both SD and low-light/LD, further suggesting that AtHSPR could be involved in the GA pathway under SD and low-light conditions. Furthermore, AtHSPR interacted in vitro with OFP1 and KNAT5, which are transcriptional repressors of GA20ox1 in GA biosynthesis. Taken together, our findings demonstrate that AtHSPR plays a positive role in GA- and light intensity-mediated regulation of flowering and seed set.
Spinoza and Judaism in the French Context: The Case of Milner’s Le Sage Trompeur*
Authors: Stetter Jack
Published: March 2020

Jean-Claude Milner’s Le sage trompeur (2013), a controversial recent piece of French Spinoza literature, remains regrettably understudied in the English-speaking world. Adopting Leo Strauss’ esoteric reading method, Milner alleges that Spinoza dissimulates his genuine analysis of the causes of the persecution and survival of the Jewish people within a brief “manifesto” found at the end of the Tractatus Theologico-Politicus (TTP), Chapter 3. According to Milner, Spinoza holds that the Jewish people themselves are responsible for the hatred of the Jewish people, and that the engine of their longevity is the hatred they engender. Additionally, claims Milner, Spinoza covertly insinuates that the solution to this persistent state of hatred consists in the mass apostasy of the Jewish people under the leadership of a Sabbatai Zevi-like figure. This article presents the Milner–Spinoza controversy to the English-speaking public along with the larger context of French-language scholarship on Spinoza’s relation to Judaism. While refuting Milner’s reading of Spinoza, I simultaneously clarify relevant elements of Spinoza’s discussions of Judaism in the TTP, such as Spinoza’s examination of Jewish identity and the nature of divine election, Spinoza’s understanding of the causes of national hatred, and Spinoza’s appeals to Portuguese, Spanish, Chinese, and Turkish political history.
Reasons for voriconazole prophylaxis discontinuation in allogeneic hematopoietic cell transplant recipients: A real-life paradigm
Authors: Chan Shuk Ying , Hughes Rachel M , Woo Kimberly , Perales Miguel-Angel , Neofytos Dionysios , Papanicolaou Genovefa
Published: March 2020

We sought to describe the clinical experience of voriconazole as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant recipients (allo-HCTr). This was a single-center retrospective study of adult allo-HCTr (1 January 2014 to 31 December 2016) who received ≥two doses of voriconazole-AFP. Voriconazole-AFP was started on day +7 post-HCT and continued at least through day +60 post-HCT, or longer as clinically indicated. We reviewed the rate, reasons, and risk factors of voriconazole-AFP discontinuation until day-100 post-HCT. A total of 327 patients were included. Voriconazole-AFP was continued for a median of 69 days (mean: 57.9; range 1, 100): for a median of 90 days (mean :84; range 2, 100) in 180/327 (55%) in the standard-of-care (SOC) group and 20 days (mean :25.6 ; range 1, 89; P-value < .001) in 147/327 (45%) patients in the early-discontinuation-group. Early-voriconazole-AFP discontinuation was due to adverse events, drug interactions, insurance coverage, and other reasons in 101/147 (68.7%), 27 (18.4%), 13 (8.8%), and 6 (4.1%) patients, respectively. Early-voriconazole-AFP discontinuation occurred in 73/327 (22.3%) patients due to hepatotoxicity. Important predictors for early-voriconazole-AFP discontinuation included: graft-versus-host disease grade ≥2 (odds ratio [OR]: 1.9, P-value: .02), alanine-aminotransferase ≥75 IU/ml on voriconazole-administration day-14 (OR: 5.6, P-value: .02) and total bilirubin ≥1.3 mg/dl on voriconazole-administration day-7 (OR: 3.0, P-value: .03). There were 13 proven/probable invasive fungal infections by day-180 post-HCT (8/147, 5.4%, and 5/180, 2.8% in the early-discontinuation and SOC-groups, respectively; log-rank:0.13). By day-180 post HCT, 23/147 (15.6%) and 14/180 (7.8%) patients in the early-discontinuation and SOC-groups had died, respectively (log-rank:0.03). Voriconazole-AFP was discontinued in up to 45% of allo-HCTr. Hepatotoxicity during the first 2 weeks post-HCT is a significant predictor of early-voriconazole-AFP discontinuation.
precision: a fast python pipeline for high-contrast imaging – application to SPHERE observations of the red supergiant VX Sagitariae
Authors: Scicluna P , Kemper F , Siebenmorgen R , Wesson R , Blommaert J A D L , Wolf S
Published: March 2020

The search for extrasolar planets has driven rapid advances in instrumentation, resulting in cameras such as SPHERE at the VLT, GPI at Gemini South and SCExAO at Subaru, capable of achieving very high contrast (∼106) around bright stars with small inner working angles (${\sim}0.1\,{\rm arcsec}$). The optimal exploitation of data from these instruments depends on the availability of easy-to-use software to process and analyse their data products. We present a pure-python pipeline, precision, which provides fast, memory-efficient reduction of data from the SPHERE/IRDIS near-infrared imager, and can be readily extended to other instruments. We apply precision to observations of the extreme red supergiant VX Sgr, the inner outflow of which is revealed to host complex, asymmetric structure in the near-IR. In addition, optical polarimetric imaging reveals clear extended polarized emission on ∼0.5 arcsec scales that varies significantly with azimuth, confirming the asymmetry. While not conclusive, this could suggest that the ejecta are confined to a disc or torus, which we are viewing nearly face on, although other non-spherical or clumpy configurations remain possible. VX Sgr has no known companions, making such a geometry difficult to explain, as there is no obvious source of angular momentum in the system.
Dark Energy Survey Year 1 Results: Wide-field mass maps via forward fitting in harmonic space
Authors: Mawdsley B , Bacon D , Chang C , Melchior P , Rozo E , Seitz S , Jeffrey N , Gatti M , Gaztanaga E , Gruen D , Hartley W G , Hoyle B , Samuroff S , Sheldon E , Troxel M A , Zuntz J , Abbott T M C , Annis J , Bertin E , Bridle S L , Brooks D , Buckley-Geer E , Burke D L , Carnero Rosell A , Carrasco Kind M , Carretero J , da Costa L N , De Vicente J , Desai S , Diehl H T , Doel P , Evrard A E , Flaugher B , Fosalba P , Frieman J , García-Bellido J , Gerdes D W , Gruendl R A , Gschwend J , Gutierrez G , Hollowood D L , Honscheid K , James D J , Jarvis M , Jeltema T , Kuehn K , Kuropatkin N , Lima M , Maia M A G , Marshall J L , Miquel R , Plazas A A , Roodman A , Sanchez E , Scarpine V , Serrano S , Sevilla-Noarbe I , Smith M , Smith R C , Sobreira F , Suchyta E , Swanson M E C , Tarle G , Tucker D L , Vikram V , Walker A R ,   (DES Collaboration)
Published: March 2020

We present new wide-field weak lensing mass maps for the Year 1 Dark Energy Survey (DES) data, generated via a forward fitting approach. This method of producing maps does not impose any prior constraints on the mass distribution to be reconstructed. The technique is found to improve the map reconstruction on the edges of the field compared to the conventional Kaiser–Squires method, which applies a direct inversion on the data; our approach is in good agreement with the previous direct approach in the central regions of the footprint. The mapping technique is assessed and verified with tests on simulations; together with the Kaiser–Squires method, the technique is then applied to data from the DES Year 1 data and the differences between the two methods are compared. We also produce the first DES measurements of the convergence Minkowski functionals and compare them to those measured in simulations.
Defying the laws of gravity I: model-independent reconstruction of the Universe expansion from growth data
Authors: L’Huillier Benjamin , Shafieloo Arman , Polarski David , Starobinsky Alexei A
Published: March 2020

Using redshift space distortion data, we perform model-independent reconstructions of the growth history of matter inhomogeneity in the expanding Universe using two methods: crossing statistics and Gaussian processes. We then reconstruct the corresponding history of the Universe background expansion and fit it to Type Ia supernovae data, putting constraints on (Ωm, 0, σ8, 0). The results obtained are consistent with the concordance flat-ΛCDM model and General Relativity as the gravity theory given the current quality of the inhomogeneity growth data.
Understanding nebular spectra of Type Ia supernovae
Authors: Wilk Kevin D , Hillier D John , Dessart Luc
Published: March 2020

In this study, we present one-dimensional, non-local-thermodynamic-equilibrium, radiative transfer simulations (using cmfgen) in which we introduce micro-clumping at nebular times into two Type Ia supernova ejecta models. We use one sub-Chandrasekhar (sub-MCh) ejecta model with 1.04 M⊙ and one Chandrasekhar (MCh) ejecta model with 1.40 M⊙. We introduce clumping factors f = 0.33, 0.25, and 0.10, which are constant throughout the ejecta, and compare results to the unclumped f = 1.0 case. We find that clumping is a natural mechanism to reduce the ionization of the ejecta, reducing emission from [Fe iii], [Ar iii], and [S iii] by a factor of a few. For decreasing values of the clumping factor f, the [Ca ii] λλ7291,7324 doublet became a dominant cooling line for our MCh model but remained weak in our sub-MCh model. Strong [Ca ii] λλ7291,7324 indicates non-thermal heating in that region and may constrain explosion modelling. Due to the low abundance of stable nickel, our sub-MCh model never showed the [Ni ii] 1.939-μm diagnostic feature for all clumping values.
A high-resolution spectroscopic study of two new Na- and Al-rich field giants–likely globular cluster escapees in the Galactic halo
Authors: Bandyopadhyay Avrajit , Thirupathi Sivarani , Beers Timothy C , Susmitha A
Published: March 2020

The stars SDSS J0646+4116 and SDSS J1937+5024 are relatively bright stars that were initially observed as a part of the SDSS/MARVELS pre-survey. They were selected, on the basis of their weak CH G bands, along with a total of 60 others, in the range of halo globular cluster (GC) metallicities for high-resolution spectroscopic follow-up as a part of the HESP-GOMPA survey (Hanle Echelle SPectrograph – Galactic survey Of Metal Poor stArs). The stars exhibit typical nucleosynthesis signatures expected from the so-called second-generation stars of GCs. The light-element anticorrelation of Mg–Al is detected, along with elevated abundances of Na. Carbon is found to be depleted, which is compatible with expectation. Lithium is also detected in SDSS J0646+4116 and SDSS J1937+5024; the measured abundances are similar to those of normal halo giant stars. These bright escapees provide a unique opportunity to study the nucleosynthesis events of GC in great detail, and shed light on their chemical-enrichment histories.
Early neutron star evolution in high-mass X-ray binaries
Authors: Ho Wynn C G , Wijngaarden M J P , Andersson Nils , Tauris Thomas M , Haberl F
Published: March 2020

The application of standard accretion theory to observations of X-ray binaries provides valuable insights into neutron star (NS) properties, such as their spin period and magnetic field. However, most studies concentrate on relatively old systems, where the NS is in its late propeller, accretor, or nearly spin equilibrium phase. Here, we use an analytic model from standard accretion theory to illustrate the evolution of high-mass X-ray binaries (HMXBs) early in their life. We show that a young NS is unlikely to be an accretor because of the long duration of ejector and propeller phases. We apply the model to the recently discovered ∼4000 yr old HMXB XMMU J051342.6−672412 and find that the system’s NS, with a tentative spin period of 4.4 s, cannot be in the accretor phase and has a magnetic field B > a few × 1013 G, which is comparable to the magnetic field of many older HMXBs and is much higher than the spin equilibrium inferred value of a few × 1011 G. The observed X-ray luminosity could be the result of thermal emission from a young cooling magnetic NS or a small amount of accretion that can occur in the propeller phase.
Candidate Population III stellar complex at z = 6.629 in the MUSE Deep Lensed Field
Authors: Vanzella E , Meneghetti M , Caminha G B , Castellano M , Calura F , Rosati P , Grillo C , Dijkstra M , Gronke M , Sani E , Mercurio A , Tozzi P , Nonino M , Cristiani S , Mignoli M , Pentericci L , Gilli R , Treu T , Caputi K , Cupani G , Fontana A , Grazian A , Balestra I
Published: March 2020

We discovered a strongly lensed (μ ≳ 40) Ly α emission at z = 6.629 (S/N ≃ 18) in the MUSE Deep Lensed Field (MDLF) targeting the Hubble Frontier Field (HFF) galaxy cluster MACS J0416. Dedicated lensing simulations imply that the Ly α emitting region necessarily crosses the caustic. The arc-like shape of the Ly α extends 3 arcsec on the observed plane and is the result of two merged multiple images, each one with a de-lensed Ly α luminosity L ≲ 2.8 × 1040 erg s−1 arising from a confined region (≲150 pc effective radius). A spatially unresolved Hubble Space Telescope(HST) counterpart is barely detected at S/N ≃ 2 after stacking the near-infrared bands, corresponding to an observed (intrinsic) magnitude m1500 ≳ 30.8 (≳35.0). The inferred rest-frame Ly α equivalent width is EW0 > 1120 Å if the IGM transmission is TIGM < 0.5. The low luminosities and the extremely large Ly α EW0 match the case of a Population III (Pop III) star complex made of several dozens stars (∼104 M⊙) that irradiate an H ii region crossing the caustic. While the Ly α and stellar continuum are among the faintest ever observed at this redshift, the continuum and the Ly α emissions could be affected by differential magnification, possibly biasing the EW0 estimate. The aforementioned tentative HST detection tends to favour a large EW0, making such a faint Pop III candidate a key target for the James Webb Space Telescope and Extremely Large Telescopes.
Chimeric siRNAs with chemically modified pentofuranose and hexopyranose nucleotides: altritol-nucleotide (ANA) containing GalNAc–siRNA conjugates: in vitro and in vivo RNAi activity and resistance to 5′-exonuclease
Authors: Kumar Pawan , Degaonkar Rohan , Guenther Dale C , Abramov Mikhail , Schepers Guy , Capobianco Marie , Jiang Yongfeng , Harp Joel , Kaittanis Charalambos , Janas Maja M , Castoreno Adam , Zlatev Ivan , Schlegel Mark K , Herdewijn Piet , Egli Martin , Manoharan Muthiah
Published: March 2020

In this report, we investigated the hexopyranose chemical modification Altriol Nucleic Acid (ANA) within small interfering RNA (siRNA) duplexes that were otherwise fully modified with the 2′-deoxy-2′-fluoro and 2′-O-methyl pentofuranose chemical modifications. The siRNAs were designed to silence the transthyretin (Ttr) gene and were conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand for targeted delivery to hepatocytes. Sense and antisense strands of the parent duplex were synthesized with single ANA residues at each position on the strand, and the resulting siRNAs were evaluated for their ability to inhibit Ttr mRNA expression in vitro. Although ANA residues were detrimental at the 5′ end of the antisense strand, the siRNAs with ANA at position 6 or 7 in the seed region had activity comparable to the parent. The siRNA with ANA at position 7 in the seed region was active in a mouse model. An Oligonucleotide with ANA at the 5′ end was more stable in the presence of 5′-exonuclease than an oligonucleotide of the same sequence and chemical composition without the ANA modification. Modeling studies provide insight into the origins of regiospecific changes in potency of siRNAs and the increased protection against 5′-exonuclease degradation afforded by the ANA modification.
Mechanisms of palmitic acid-conjugated antisense oligonucleotide distribution in mice
Authors: Chappell Alfred E , Gaus Hans J , Berdeja Andres , Gupta Ruchi , Jo Minji , Prakash Thazha P , Oestergaard Michael , Swayze Eric E , Seth Punit P
Published: March 2020

Conjugation of antisense oligonucleotide (ASO) with a variety of distinct lipophilic moieties like fatty acids and cholesterol increases ASO accumulation and activity in multiple tissues. While lipid conjugation increases tissue exposure in mice and reduces excretion of ASO in urine, histological review of skeletal and cardiac muscle indicates that the increased tissue accumulation of lipid conjugated ASO is isolated to the interstitium. Administration of palmitic acid-conjugated ASO (Palm-ASO) in mice results in a rapid and substantial accumulation in the interstitium of muscle tissue followed by relatively rapid clearance and only slight increases in intracellular accumulation in myocytes. We propose a model whereby increased affinity for lipid particles, albumin, and other plasma proteins by lipid-conjugation facilitates ASO transport across endothelial barriers into tissue interstitium. However, this increased affinity for lipid particles and plasma proteins also facilitates the transport of ASO from the interstitium to the lymph and back into circulation. The cumulative effect is only a slight (∼2-fold) increase in tissue accumulation and similar increase in ASO activity. To support this proposal, we demonstrate that the activity of lipid conjugated ASO was reduced in two mouse models with defects in endothelial transport of macromolecules: caveolin-1 knockout (Cav1−/−) and FcRn knockout (FcRn−/−).
SuperCYPsPred—a web server for the prediction of cytochrome activity
Authors: Banerjee Priyanka , Dunkel Mathias , Kemmler Emanuel , Preissner Robert
Published: March 2020

Cytochrome P450 enzymes (CYPs)-mediated drug metabolism influences drug pharmacokinetics and results in adverse outcomes in patients through drug–drug interactions (DDIs). Absorption, distribution, metabolism, excretion and toxicity (ADMET) issues are the leading causes for the failure of a drug in the clinical trials. As details on their metabolism are known for just half of the approved drugs, a tool for reliable prediction of CYPs specificity is needed. The SuperCYPsPred web server is currently focused on five major CYPs isoenzymes, which includes CYP1A2, CYP2C19, CYP2D6, CYP2C9 and CYP3A4 that are responsible for more than 80% of the metabolism of clinical drugs. The prediction models for classification of the CYPs inhibition are based on well-established machine learning methods. The models were validated both on cross-validation and external validation sets and achieved good performance. The web server takes a 2D chemical structure as input and reports the CYP inhibition profile of the chemical for 10 models using different molecular fingerprints, along with confidence scores, similar compounds, known CYPs information of drugs—published in literature, detailed interaction profile of individual cytochromes including a DDIs table and an overall CYPs prediction radar chart (http://insilico-cyp.charite.de/SuperCYPsPred/). The web server does not require log in or registration and is free to use.
Immune Checkpoint Inhibitors for Brain Metastases: A Primer for Neurosurgeons
Authors: Aquilanti Elisa , Brastianos Priscilla K
Published: March 2020

Immune checkpoint inhibitors enhance immune recognition of tumors by interfering with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD1) pathways. In the past decade, these agents brought significant improvements to the prognostic outlook of patients with metastatic cancers. Recent data from retrospective analyses and a few prospective studies suggest that checkpoint inhibitors have activity against brain metastases from melanoma and nonsmall cell lung cancer, as single agents or in combination with radiotherapy. Some studies reported intracranial response rates that were comparable with systemic ones. In this review, we provide a comprehensive summary of clinical data supporting the use of anti-CTLA4 and anti-PD1 agents in brain metastases. We also touch upon specific considerations on the assessment of intracranial responses in patients and immunotherapy-specific toxicities. We conclude that a subset of patients with brain metastases benefit from the addition of checkpoint inhibitors to standard of care therapeutic modalities, including radiotherapy and surgery.
Rules versus Discretion in Bank Resolution
Authors: Walther Ansgar , White Lucy
Published: March 2020

Recent reforms have given regulators broad powers to “bail-in” bank creditors during financial crises. We analyze efficient bail-ins and their implementation. To preserve liquidity, regulators must avoid signaling negative private information to creditors. Therefore, optimal bail-ins in bad times only depend on public information. As a result, the optimal policy cannot be implemented if regulators have wide discretion, due to an informational time-inconsistency problem. Rules mandating tough bail-ins after bad public signals, or contingent convertible (co-co) bonds, improve welfare. We further show that bail-in and bailout policies are complementary: if bailouts are possible, then discretionary bail-ins are more effective.
Love Carefully and Without ‘Over-bearing Fears’: The Persuasive Power of Authenticity in Late 1980s British AIDS Education Material for Adolescents
Authors: Elizabeth Hannah J
Published: March 2020

This article examines the 1987 British AIDS education leaflet Love Carefully: Use a condom, drawing on methodologies from both the history of emotion and literary analysis. The informative leaflet, produced collaboratively by the sexual health charities Brook and the Family Planning Association, was intended to prevent the spread of HIV among heterosexual adolescents, a group increasingly viewed as ‘at risk’ by adult producers of health education globally. Steeped in British teenage popular culture, it deployed an introduction from well-known teenage agony aunt Melanie McFadyean, a cartoon strip, and statements from celebrities. The cartoon offered a representation of the difficulties experienced by heterosexual teenagers negotiating the prospect of penetrative sex with a new partner, offering a successful example of condom negotiation, while sympathetically examining why some found condom use and AIDS difficult subjects to broach. The article argues the leaflet deployed emotions and authenticity to persuade teenagers to practise safer sex.
The Mother-Based Intervention: Policy, Social Work, and the Absence of Fathers in the Social Services in Israel
Authors: Perez-Vaisvidovsky Nadav , Mizrahi Reli , Halpern Ayana
Published: March 2020

The increasing scholarly interest in the absence of fathers from family-focused interventions by the social services tends to focus on the role of fathers, mothers, and social workers in this absence. The role of policymakers, however, has been neglected. This article examines the case study of policymakers in the Israeli social services to fill in this gap and examine the role of policy and policymakers in fathers’ absence. The findings reveal that policy is based on the ‘mother-based intervention’ assumption—the services are built around the assumption that interventions include only mothers, and therefore make engaging fathers an exception.
Effect of combinations of feed-grade urea and slow-release urea in a finishing beef diet on fermentation in an artificial rumen system
Authors: Alipour Daryoush , Saleem Atef Mohamed , Sanderson Haley , Brand Tassilo , Santos Laize V , Mahmoudi-Abyane Mahdi , Marami Mohammad Reza , McAllister Tim Angus
Published: March 2020

This study evaluated the effect of combinations of feed-grade urea and slow-release urea (SRU) on fermentation and microbial protein synthesis within two artificial rumens (Rusitec) fed a finishing concentrate diet. The experiment was a completely randomized, dose–response design with SRU substituted at levels of 0% (control), 0.5%, 1%, or 1.75% of dry matter (DM) in place of feed-grade urea, with four replicate fermenters per dosage. The diet consisted of 90% concentrate and 10% forage (DM basis). The experiment was conducted over 15 d, with 8 d of adaptation and 7 d of sampling. Dry matter and organic matter disappearances were determined after 48 h of incubation from day 9 to 12, and daily ammonia (NH3) and volatile fatty acid (VFA) production were measured from day 9 to 12. Microbial protein synthesis was determined on days 13–15. Increasing the level of SRU quadratically affected total VFA (Q, P = 0.031) and ammonia (Q, P = 0.034), with a linear increment in acetate (L, P = 0.01) and isovalerate (L, P = 0.05) and reduction in butyrate (L, P = 0.05). Disappearance of neutral detergent fiber (NDF) and acid detergent fiber (ADF) was quadratically affected by levels of SRU, plateauing at 1% SRU. Inclusion of 1% SRU resulted in the highest amount of microbial nitrogen associated with feed particles (Q, P = 0.037). Responses in the efficiency of microbial protein synthesis fluctuated (L, P = 0.002; Q, P = 0.001) and were the highest for 1% SRU. In general, the result of this study showed that 1% SRU in combination with 0.6% urea increased NDF and ADF digestibility and total volatile fatty acid (TVFA) production.
Association Between Patterns of Alcohol Use and Short-Term Risk of Suicide Attempt Among Patients With and Without Reported Suicidal Ideation
Authors: Richards Julie E. , Shortreed Susan M. , Simon Greg E. , Penfold Robert B. , Glass Joseph E. , Ziebell Rebecca , Williams Emily C.
Published: March 2020

Objective:

To evaluate the association between patterns of alcohol use and short-term risk of suicide attempt among patients with and without reported suicidal ideation.

Methods:

Kaiser Permanente Washington electronic health record data were used to identify mental health visits (1/1/2010-6/30/2015) with documented assessments for unhealthy alcohol use (AUDIT-C) and suicidal ideation (PHQ-9 ninth question). Logistic regression fit using generalized estimating equations were used to conduct visit-level analyses, accounting for correlation between individuals’ assessments. Separate models evaluated the association between (1) level of alcohol consumption and (2) frequency of heavy episodic drinking (HED), in combination with suicidal ideation (any vs none), with suicide attempt within 90 days following each visit. Primary models adjusted for age, gender, race/ethnicity and visit year.

Results:

Of 59,705 visits (43,706 unique patients), 372 (0.62%) were followed by a suicide attempt within 90 days. The risk of suicide attempt was significantly higher for patients reporting suicidal ideation across all levels of alcohol consumption compared to patients reporting low-level alcohol use and no suicidal ideation, particularly high-level use (OR 9.77, 95% CI, 6.23–15.34). Similarly, risk of suicide attempt was higher for patients reporting suicidal ideation across all levels of HED relative to those reporting no HED or suicidal ideation, particularly HED monthly or more (OR 6.80, 95% CI 4.77–9.72). Among patients reporting no suicidal ideation, no associations were observed.

Conclusions:

Findings underscore the potential value of offering alcohol-related care to patient reporting suicidal ideation. Additional strategies are needed to identify suicide risk among those reporting no suicidal ideation.
Challenges for hepatitis B virus cure in resource-limited settings in sub-Saharan Africa
Authors: Kramvis Anna
Published: March 2020

Purpose of review

The aim of this article is to highlight the unique challenges for hepatitis B virus (HBV) cure faced in resource-limited settings (RLS) in sub-Saharan Africa (SSA), where access to disease prevention measures, medical testing, and treatment are limited.

Recent findings

SSA RLS face challenges, which need to be anticipated as HBV cure research advances. There is a paucity of data because of lack of HBV surveillance and limited access to laboratories. Interruption of transfusion-transmitted infections, perinatal mother-to-child-transmissions, and transmission in people-who-infect-drug networks has not been achieved fully. Although RLS in SSA are within the epicenter of the HIV pandemic, unlike for HIV, there is no population-based testing for HBV. Public health response to HBV is inadequate with concomitant political inertia in combatting HBV infection.

A functional HBV cure will improve the diagnosis/treatment cascade, decrease costs and accelerate HBV elimination. There is a concerted effort to find a HBV cure, which will be finite, not require life-long treatment, adherence, and continued monitoring. Increased research, improved financial, infrastructural and human resources will positively impact on implementation of HBV cure, when available. We can emulate major strides made in tackling HIV and the strength of advocacy groups in soliciting policymakers to take action.
Ursolic Acid Improves Monocrotaline-Induced Right Ventricular Remodeling by Regulating Metabolism
Authors: Gao Xiaojian , Zhang Zeyu , Li Xin , Wei Qingxia , Li Hanlu , Li Chen , Chen Haixu , Liu Chunlei , He Kunlun
Published: March 2020

Pulmonary arterial hypertension (PAH) is a progressive and malignant disease characterized by pulmonary small arteries and right ventricle (RV) remodeling that can lead to severe RV dysfunction and death. The current therapeutic targets for RV dysfunction, which is strongly linked to mortality, are far from adequate. Therefore, we investigated the effect of ursolic acid (UA), a pentacyclic triterpenoid carboxylic acid, on PAH-induced RV remodeling and its underlying mechanism. We established a PAH model by injecting Sprague Dawley rats with monocrotaline (MCT, 60 mg/kg, ip), as verified by echocardiography and hemodynamic examination. Proteomic analysis was performed on RV samples using a Q Exactive high-field mass spectrometer, followed by KEGG enrichment analysis. The effect of 4 weeks of UA (50 mg/kg) treatment on RV remodeling was explored based on ultrasound, hemodynamic parameters, and histological changes, with the mechanism verified in vivo and in vitro by qRT-PCR and western blotting. RV hypertrophy, fibrosis, increased apoptosis, and abnormal metabolism were induced by MCT and suppressed by UA via a mechanism that changed the expression of key markers. UA also attenuated the Phenylephrine-induced hypertrophy of neonatal rat ventricular myocytes and upregulated peroxisome proliferator-activated receptor-alpha (PPARα), a key fatty acid metabolism regulator, and its downstream factor carnitine palmitoyl transferase 1b. In conclusion, UA exerts beneficial effects on PAH-induced RV dysfunction and remodeling by regulating PPARα-dependent fatty acid metabolism.
The prevalence of masked hypertension in relation to cigarette smoking in a Chinese male population
Authors: Zhang Dong-Yan , Huang Jian-Feng , Kang Yuan-Yuan , Dou Yu , Su Yan-Lun , Zhang Li-Juan , Cheng Yi-Bang , Guo Qian-Hui , Huang Qi-Fang , Li Yan , Wang Ji-Guang
Published: March 2020

Background:

Smokers may smoke cigarettes during ambulatory or home blood pressure (BP) monitoring but not clinic measurement. We investigated the prevalence of masked hypertension in relation to cigarette smoking in Chinese outpatients enrolled in a multicenter registry.

Methods:

Our study included 1646 men [494 (30.0%) current smokers]. We defined masked hypertension as a normal clinic SBP/DBP (<140/90 mmHg) and elevated daytime (≥135/85 mmHg) or night-time (≥120/70 mmHg) ambulatory or morning or evening home SBP/DBP (≥135/85 mmHg).

Results:

In all men, multiple logistic regression showed that current cigarette smoking was significantly associated with daytime [prevalence 18.7%, odds ratio (OR) 1.69, 95% confidence interval 1.27–2.25, P = 0.0003] but not night-time (prevalence 27.1%, P = 0.32) ambulatory masked hypertension and associated with evening (prevalence 14.6%, OR 1.81, confidence interval 1.33–2.47, P = 0.0002) but not morning (prevalence 17.6%, P = 0.29) home masked hypertension. The associations were more pronounced for heavy smoking (≥20 cigarettes/day) relative to never smoking for both masked daytime ambulatory (OR 1.97, P = 0.001) and evening home hypertension (OR 2.40, P < 0.0001) or in patients over 55 years of age (P for interaction in relation to daytime ambulatory masked hypertension = 0.005). In men with clinic normotension (n = 742), the associations were also significant (P < 0.01), particularly in those with a normal to high-normal clinic BP (n = 619, P < 0.04).

Conclusion:

Cigarette smoking was associated with increased odds of masked daytime ambulatory and evening home hypertension, especially in heavy smoking or older men.
Clinical Profile of Bilateral Microsporidial Keratoconjunctivitis in Healthy Individuals—A Case Series With Long-term Follow-up
Authors: Mohanty Amrita , Mitra Sanchita , Das Sujata , Priyadarshini Smrutirekha , Sahu Srikant K.
Published: March 2020

Purpose:

To describe bilateral microsporidial keratoconjunctivitis in healthy individuals with long-term follow-up.

Methods:

Six cases of smear-positive bilateral microsporidial keratoconjunctivitis were diagnosed and followed up during the study period August 2017 to January 2019. Associated risk factors, clinical features, coexistence with adenovirus, clinical course, and recurrence were studied.

Results:

The mean age was 36.6 years (range: 10–65 years). The mean duration of symptoms was 13.6 days (range: 7–60 days). Predisposing risk factors were present in 4 of 6 cases. The best-corrected visual acuity at presentation was ≥20/30 in all eyes except in one. Typical microsporidial epithelial lesions were seen in only one case. Persistent lesions, clinically resembling Thygeson superficial punctate keratitis in both eyes, were observed in 3 cases. The lesions in 5 eyes resolved with topical lubricants, and the remaining 7 eyes were treated with topical steroids and tacrolimus 0.03%. Complete resolution was seen in 5 eyes at the end of 1 month, and superficial scarring at the last follow-up was seen in 5 eyes. The best-corrected visual acuity was ≤20/30 in 3 eyes at the last follow-up. The mean duration of follow-up was 7.3 months (range: 3–12 mo).

Conclusions:

Bilateral microsporidial keratoconjunctivitis in healthy patients has an atypical presentation with prolonged course. Microsporidia could be implicated as potential candidates in the etiopathogenesis of Thygeson superficial punctate keratitis.
Epithelial Plaque Formation Secondary to Recombinant Human Nerve Growth Factor
Authors: Weinlander Eric , Ling Jennifer , Reddy Aparna , Nallasamy Nambi
Published: March 2020

Purpose:

To report a case of corneal epithelial plaque formation associated with recombinant human nerve growth factor (cenegermin 0.002%; Oxervate, Dompé US Inc., Boston, MA), an as-yet unreported adverse event.

Methods:

A case report and review of literature.

Results:

A 45-year-old woman presented with a nonhealing 3.25- × 4.25-mm corneal epithelial defect secondary to multifactorial neurotrophic keratitis in the right eye. The epithelial defect was resistant to maximal medical therapy, and so cenegermin 0.002% was initiated, resulting in resolution of the corneal epithelial defect. After 6.5 weeks of treatment, she developed an unusual corneal epithelial plaque, decreased visual acuity, and eye pain. Cenegermin was ceased, after which the lesion resolved, visual acuity improved, and eye pain resolved.

Conclusions:

Cenegermin 0.002% has emerged as a promising treatment for neurotrophic keratitis. Reported adverse events with this agent have been minor and typically not vision threatening. Here, we describe corneal epithelial plaque formation as a visually significant adverse event that resolved with cessation of cenegermin 0.002%. Although the underlying mechanism is unknown, clinicians should be alerted to the possibility of epithelial plaque formation in patients being treated with recombinant human nerve growth factor for neurotrophic keratitis.
Intraoperative Optical Coherence Tomography–Assisted Descemet Membrane Endothelial Keratoplasty: Toward More Efficient, Safer Surgery
Authors: Muijzer Marc B. , Soeters Nienke , Godefrooij Daniel A. , van Luijk Chantal M. , Wisse Robert P. L.
Published: March 2020

Purpose:

To evaluate the clinical value of intraoperative optical coherence tomography (iOCT) and prolonged overpressure in Descemet membrane endothelial keratoplasty for surgical safety, efficiency, and outcome.

Methods:

All Descemet membrane endothelial keratoplasties performed by the same surgeon from November 2016 through April 2018 at the University Medical Center Utrecht were included, including 6 months of follow-up. The primary outcome was the prevalence of adverse events, and the secondary outcomes included critical decision-making and surgery time. Surgeries that included prolonged (ca. 12 minutes) overpressurization of the globe were classified as group 1, and those without prolonged overpressurization of the globe were classified as group 2. In all cases, iOCT was used to determine the graft orientation, apposition, and assessment of interface fluid.

Results:

A total of 38 cases were included for analysis. In groups 1 and 2, 7 (43.6%) and 4 (18.1%) adverse events, respectively, were recorded (P = 0.29). Specifically, in groups 1 and 2, 4 and 3 cases, respectively, required rebubbling because of graft dislocation (P = 0.15). In 43% of surgeries, iOCT proved to be of value for surgical decision-making. Surgery time differed significantly between groups 1 and 2 (P < 0.001) and was the result of a shortened pressurization time in group 2.

Conclusions:

iOCT provides a direct assessment of the graft orientation and apposition, allowing the surgeon to refrain from prolonged pressurization of the globe after graft insertion. Optimizing the surgical protocol using iOCT can lead to a significant reduction in surgery time without compromising surgical safety or outcome.
Erythrocyte adaptive metabolic reprogramming under physiological and pathological hypoxia
Authors: D’Alessandro Angelo , Xia Yang
Published: March 2020

Purpose of review

The erythrocyte is the most abundant cell type in our body, acting as both a carrier/deliverer and sensor of oxygen (O2). Erythrocyte O2 delivery capacity is finely regulated by sophisticated metabolic control. In recent years, unbiased and robust human metabolomics screening and mouse genetic studies have advanced erythroid research revealing the differential role of erythrocyte hypoxic metabolic reprogramming in normal individuals at high altitudes and patients facing hypoxia, such as sickle cell disease (SCD) and chronic kidney disease (CKD). Here we summarize recent progress and highlight potential therapeutic possibilities.

Recent findings

Initial studies showed that elevated soluble CD73 (sCD73, converts AMP to adenosine) results in increased circulating adenosine that activates the A2B adenosine receptor (ADORA2B). Signaling through this axis is co-operatively strengthened by erythrocyte-specific synthesis of sphingosine-1-phosphate (S1P). Ultimately, these mechanisms promote the generation of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific allosteric modulator that decreases haemoglobin--O2-binding affinity, and thus, induces deoxygenated sickle Hb (deoxyHbS), deoxyHbS polymerization, sickling, chronic inflammation and tissue damage in SCD. Similar to SCD, plasma adenosine and erythrocyte S1P are elevated in humans ascending to high altitude. At high altitude, these two metabolites are beneficial to induce erythrocyte metabolic reprogramming and the synthesis of 2,3-BPG, and thus, increase O2 delivery to counteract hypoxic tissue damage. Follow-up studies showed that erythrocyte equilibrative nucleoside transporter 1 (eENT1) is a key purinergic cellular component controlling plasma adenosine in humans at high altitude and mice under hypoxia and underlies the quicker and higher elevation of plasma adenosine upon re-ascent because of prior hypoxia-induced degradation of eENT1. More recent studies demonstrated the beneficial role of erythrocyte ADORA2B-mediated 2,3-BPG production in CKD.

Taken together, these findings revealed the differential role of erythrocyte hypoxic metabolic reprogramming in normal humans at high altitude and patients with CKD vs. SCD patients and immediately suggest differential and precision therapies to counteract hypoxia among these groups.
Ileal conduit or orthotopic neobladder: selection and contemporary patterns of use
Authors: Almassi Nima , Bochner Bernard H.
Published: March 2020

Purpose of review

The orthotopic neobladder and ileal conduit are the two most commonly utilized urinary diversions among patients undergoing radical cystectomy. Although orthotopic diversion offers several advantages, only 20% of patients nationally receive this diversion, with decreasing utilization over time. The purpose of this article is to review advantages of each diversion type and considerations in patient selection, review trends in diversion utilization and perioperative and functional outcomes, and examine recent studies evaluating methods of optimizing diversion selection and patient satisfaction and outcomes.

Recent findings

Decreasing utilization of orthotopic diversion has coincided with the increasing utilization of minimally invasive surgical techniques. A multicentre robotic series demonstrated a higher incidence of high-grade complications with intracorporeal diversion, reflecting the learning-curve associated with this technique. Patient satisfaction with urinary diversion is associated with informed decision-making and goal alignment. Ongoing quality of life studies is aiming to identify predictors of patient satisfaction with the selected urinary diversion and may help guide patient counselling.

Given the potential advantages of orthotopic diversion, its decreasing use is a concerning trend. Elucidating patient goals and informed decision-making are critical to patient satisfaction. A patient-centred approach should be used when selecting the type of urinary diversion for a given patient.