bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of medium chain fatty acids as a mitigation or prevention strategy against porcine epidemic diarrhea virus in swine feed
Authors: Lerner Annie B , Cochrane Roger A , Gebhardt Jordan T , Dritz Steve S , Jones Cassandra K , DeRouchey Joel M , Tokach Mike D , Goodband Robert D , Bai Jianfa , Porter Elizabeth , Anderson Joe , Gauger Phillip C , Magstadt Drew R , Zhang Jianqiang , Bass Benjamin , Karnezos Theodore , de Rodas Brenda , Woodworth Jason C
Published: May 2020

Feed has been shown to be a vector for viral transmission. Four experiments were conducted to: 1) determine if medium chain fatty acids (MCFA) are effective mitigants when applied to feed both pre- and post-porcine epidemic diarrhea virus (PEDV) inoculation measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR), 2) evaluate varying levels and combinations of MCFA measured by qRT-PCR, and 3) evaluate selected treatments in bioassay to determine infectivity. In exp. 1, treatments were arranged in a 2 × 2 + 1 factorial with main effects of treatment (0.3% commercial formaldehyde [CF] product, Sal CURB [Kemin Industries, Inc.; Des Moines, IA], or 1% MCFA blend (Blend) of 1:1:1 C6:C8:C10 [PMI, Arden Hills, MN]) and timing of application (pre- or post-inoculation with PEDV) plus a positive control (PC; feed inoculated with PEDV and no treatment). All combinations of treatment and timing decreased detectable PEDV compared with the PC (P < 0.05). Pre-inoculation treatment elicited decreased magnitude of PEDV detection (cycle threshold value) compared with post-inoculation (P = 0.009). Magnitude of PEDV detection was decreased for CF compared with Blend (P < 0.0001). In exp. 2, pre-inoculation treatments consisted of: 1) PC, 2) 0.3% CF, 3 to 5) 0.125% to 0.33% C6:0, 6 to 8) 0.125% to 0.33% C8:0, 9 to 11) 0.125% to 0.33% C10:0, and 12 to 15) 0.125% to 0.66% C5:0. Treating feed with 0.33% C8:0 resulted in decreased (P < 0.05) PEDV detection compared with all other treatments. Increasing concentration of each individual MCFA decreased PEDV detectability (P < 0.042). In exp. 3, pre-inoculation treatments consisted of: 1) PC, 2) 0.3% CF, 3 to 7) 0.25% to 1% Blend, 8 to 10) 0.125% to 0.33% C6:0 + C8:0, 11 to 13) 0.125% to 0.33% C6:0 + C10:0, and 14 to 16) 0.125% to 0.33% C8:0 + C10:0. Treating feed with CF, 0.5% Blend, 0.75% Blend, 1% Blend, all levels of C6:0+C8:0, 0.25% C6:0 + 0.25% C10:0, 0.33% C6:0 + 0.33% C10:0, 0.25% C8:0 + 0.25% C10:0, or 0.33% C8:0 + 0.33% C10:0 elicited decreased detection of PEDV compared with PC (P < 0.05). Increasing concentration of each MCFA combination decreased PEDV detectability (linear, P < 0.012). In exp. 4, feed was treated pre-inoculation with: 1) no treatment (PC), 2) 0.3% CF, 3) 0.5% Blend, or 4) 0.3% C8:0 and analyzed via qRT-PCR and bioassay. Adding 0.5% Blend or 0.3% C8:0 resulted in decreased PEDV compared with PC and only PC resulted in a positive bioassay. Therefore, MCFA can decrease detection of PEDV in feed. Further, inclusion of lower levels of MCFA than previously evaluated are effective against PEDV.
Optimum roughage proportion in barley-based feedlot cattle diets: total tract nutrient digestibility, rumination, ruminal acidosis, short-chain fatty absorption, and gastrointestinal tract barrier function
Authors: Chibisa Gwinyai E , Beauchemin Karen A , Koenig Karen M , Penner Gregory B
Published: May 2020

Cattle need physically effective fiber to promote rumination and maintain rumen health, but economics favor the use of low-roughage feedlot diets. The study investigated the optimum barley silage proportion in barley-based finishing diets. Apparent total-tract digestibility (4-d total fecal collection), chewing behavior (6-d video recording), ruminal pH (6-d indwelling pH recording), and fermentation (1 day, sampling 0, 3, 6, 12, and 18 h postfeeding), short-chain fatty acid (SCFA) absorption (washed reticulo-rumen technique), gastrointestinal tract barrier function (marker infusion), and blood variables (catheters) were measured. Eight ruminally fistulated crossbred beef heifers (653 ± 44.2 kg; mean starting body weight [BW] ± SD) were used in a replicated 4 × 4 Latin square design with 28-d periods. Dietary treatments were 0%, 4%, 8%, and 12% of dietary dry matter (DM) as barley silage, with diets containing 80%, 76%, 72%, and 68% barley grain, respectively. Increasing silage proportion decreased dietary starch content from 49.0% to 43.1% DM, while neutral detergent content increased from 22.7% to 25.1% DM. Silage proportion had no effect on DM intake, but apparent DM digestibility decreased quadratically (86.0%, 82.1%, 81.1%, 79.5% for the four diets, respectively; P < 0.001). Although, silage proportion had no effect on eating activity, rumination time increased quadratically (246, 289, 302, 316 min/d; P = 0.04). Increased silage proportion increased minimum (5.07, 5.27, 5.29, 5.41; quadratic, P = 0.011) and mean (5.61, 5.87, 5.93, 5.95; quadratic, P = 0.007) ruminal pH, and there was a quadratic (P ≤ 0.047) decrease in duration and area under the pH acidosis threshold curves of 5.8, 5.5, and 5.2. Although increasing silage proportion decreased ruminal acidosis, it was not completely eliminated even with a diet containing 12% silage DM. SCFA concentration in ruminal fluid was not affected by diet, but silage proportion quadratically (P ≤ 0.088) increased ruminal acetate:propionate. There was no effect of diet on absolute or fractional rates of absorption of acetate, propionate, butyrate or total SCFA, and no effect on gastrointestinal barrier function or blood measurements. In conclusion, responses to roughage level were mostly quadratic with greatest improvements in acidosis variables between 0% and 4% barley silage, with incremental improvements with further increases in silage levels. The study showed a trade-off between maximizing digestibility and energy intake to promote animal performance and minimizing the risk of acidosis.
Managing Allium Leafminer (Diptera: Agromyzidae): An Emerging Pest of Allium Crops in North America
Authors: Nault Brian A , Iglesias Lindsy E , Harding Riley S , Grundberg Ethan A , Rusinek Teresa , Elkner Tim E , Lingbeek Brandon J , Fleischer Shelby J
Published: May 2020

Allium leafminer, Phytomyza gymnostoma Loew, is the newest invasive pest of allium crops in North America. Larvae initially feed in the upper canopy before mining toward the base of the plant to pupate. Crop loss occurs when larvae destroy vascular tissue, facilitating infection by bacterial and fungal pathogens that cause rot. Contamination also occurs when larvae and pupae are present at harvest. In response to this invasion, efficacy of 14 insecticide active ingredients applied via foliar sprays, transplant treatments, and drip chemigation was evaluated for managing P. gymnostoma. Multiple field studies were conducted in onions, leeks, and scallions in Pennsylvania and New York, United States in 2018 and 2019. The highest and most consistent levels of P. gymnostoma control occurred using foliar applications of dinotefuran, cyantraniliprole and spinetoram (84–89% reduction in damage; 95% reduction in P. gymnostoma densities). Despite the success of dinotefuran and cyantraniliprole applied as foliar sprays, neither was effective in controlling P. gymnostoma when administered via drip chemigation. Other foliar-applied insecticides that significantly reduced densities of P. gymnostoma in one or two experiments included abamectin, acetamiprid, cyromazine, imidacloprid, lambda-cyhalothrin, methomyl, and spinosad. Active ingredients that never controlled P. gymnostoma included azadirachtin, kaolin clay, pyrethrin, and spirotetramat. Spinosad applied to bare-root and plug-tray transplants immediately before transplanting reduced P. gymnostoma damage in the field by >90%. Implications of using these insecticides and application strategies are discussed within the context of developing a sustainable IPM program.
Mitogenomes Reveal Multiple Colonization of Mountains by Rattus in Sundaland
Authors: Camacho-Sanchez Miguel , Leonard Jennifer A
Published: May 2020

Tropical mountains are cradles of biodiversity and endemism. Sundaland, tropical Southeast Asia, hosts 3 species of Rattus endemic to elevations above 2000 m with an apparent convergence in external morphology: Rattus korinchi and R. hoogerwerfi from Sumatra, and R. baluensis from Borneo. A fourth one, R. tiomanicus, is restricted to lowland elevations across the whole region. The origins of these endemics are little known due to the absence of a robust phylogenetic framework. We use complete mitochondrial genomes from the 3 high altitude Rattus, and several related species to determine their relationships, date divergences, reconstruct their history of colonization, and test for selection on the mitochondrial DNA. We show that mountain colonization happened independently in Borneo (<390 Kya) and Sumatra (~1.38 Mya), likely from lowland lineages. The origin of the Bornean endemic R. baluensis is very recent and its genetic diversity is nested within the diversity of R. tiomanicus. We found weak evidence of positive selection in the high-elevation lineages and attributed the greater nonsynonymous mutations on these branches (specially R. baluensis) to lesser purifying selection having acted on the terminal branches in the phylogeny.
Virtues and Principles in Biomedical Ethics
Authors: Garcia Jorge L A
Published: May 2020

In the seventh and most recent edition of their classic book, Principles of Biomedical Ethics, Tom Beauchamp and James Childress define a virtue as a character trait that is “socially valuable and reliably present” and a moral virtue as such a trait that is also both “dispositional” and “morally valuable” (2013, 31, 377). The virtues that they single out as “focal” within biomedical ethics are compassion, discernment, trustworthiness, integrity, and conscientiousness (Beauchamp and Childress, 2013, 37–44). Not all is well in their treatment of virtue. Beauchamp and Childress seem to worry that an ethical theory in which virtues are fundamental will neglect duties, rights, and societal needs. Further, they insist that there is no reason to think that, within ethical theory, one family of ethical concepts is the most important, nor that one theoretical approach is correct, or even superior to others. I will try to show, that there are (and that we have) strong reasons to see language, concepts, and matters of virtue as fundamental within normative ethical theory, both generally and in such specialized subareas as medical ethics. These reasons reveal themselves when we analyze concepts at the core of the alternative approaches to theorizing ethics that Beauchamp and Childress identify.
Multisystem Inflammatory Syndrome in Children During the Coronavirus 2019 Pandemic: A Case Series
Authors: Chiotos Kathleen , Bassiri Hamid , Behrens Edward M , Blatz Allison M , Chang Joyce , Diorio Caroline , Fitzgerald Julie C , Topjian Alexis , John Audrey R Odom
Published: May 2020

We present a series of 6 critically ill children with multisystem inflammatory syndrome in children. Key findings of this syndrome include fever, diarrhea, shock, and variable presence of rash, conjunctivitis, extremity edema, and mucous membrane changes.
Modified Glasgow prognostic score can predict survival of muscle invasive bladder cancer patients after radiotherapy
Authors: Kikuchi Koyo , Nakamura Ryuji , Segawa Takafumi , Oikawa Hirobumi , Ariga Hisanori
Published: May 2020

In patients with various cancers, modified Glasgow prognostic score (mGPS) before treatment has predicted prognoses after antitumor therapy. This study aimed to assess whether pretreatment mGPS also has predictive value in patients with muscle-invasive bladder cancer (MIBC) after radiotherapy. A retrospective review accumulated 98 consecutive MIBC patients treated with definitive 3D-conformal radiotherapy from January 2011 to December 2016 in a single center. It included cT2-4bN0-3M0 patients with a median age of 79 years (range: 49 to 95 years). Radiotherapy was delivered at 60–66 Gy for bladder cancer. Patients were categorized in terms of their pretreatment serum albumin and C-reactive protein (CRP) values as mGPS_0, mGPS_1, and mGPS_2. Among them, cumulative overall survival (OS) rates were compared by Kaplan–Meier plots with log-rank tests. The number of patients with mGPS_0, mGPS_1, and mGPS_2 were 40, 40, and 18, respectively. The median follow-up time for all patients was 19 months (range: 2–73 months). The 2-year OS rate for all patients was 75.7%. The 2-year OS rates for mGPS_0, mGPS_1, and mGPS_2 were 85.1%, 71.3%, and 60.9%, respectively. Kaplan–Meier curves revealed a significantly higher cumulative OS rate for mGPS_0 compared with mGPS_1 and mGPS_2 (P = 0.003). Using multivariate Cox regression analysis, mGPS_0 and good performance status were associated with favorable OS rates, of which mGPS_0 was more significant (Hazard ratio 2.74, 95% CI 1.30–5.57, P = 0.008). Modified Glasgow prognostic score may be a novel biomarker that can predict survival in patients with MIBC after radiotherapy.
Spectropolarimetric follow-up of 8 rapidly rotating, X-ray bright FK Comae candidates
Authors: Sikora J , Rowe J , Howell S B , Mason E , Wade G A
Published: May 2020

Our understanding of the evolved, rapidly rotating, magnetically active, and apparently single FK Comae stars is significantly hindered by their extreme rarity: only two stars in addition to FK Com itself are currently considered to be members of this class. Recently, a sample of more than 20 candidate FK Comae type stars was identified within the context of the Kepler–Swift Active Galaxies and Stars (KSwAGS) survey. We present an analysis of high-resolution Stokes V observations obtained using ESPaDOnS@CFHT for 8 of these candidates. We found that none of these targets can be considered members of the FK Comae class based primarily on their inferred rotational velocities and on the detection of spectroscopic binary companions. However, 2 targets show evidence of magnetic activity and have anomalously high projected rotational velocities (vsin i) relative to typical values associated with stars of similar evolutionary states. EPIC 210426551 has a $v\sin {i}=209\, {\rm km\, s}^{-1}$, an estimated mass of $1.07\, \mathrm{ M}_\odot$, and, based in part on its derived metallicity of [M/H] = −0.4, it is either an evolved main sequence (MS) star or a pre-MS star. KIC 7732964 has a mass of $0.84\, \mathrm{ M}_\odot$, lies near the base of the red giant branch, and exhibits a $v\sin {i}=23\, {\rm km\, s}^{-1}$. We find that these two objects have similar characteristics to FK Com (albeit less extreme) and that their rapid rotation may be inconsistent with that predicted for a single star evolutionary history. Additional observations are necessary in order to better constrain their evolutionary states and whether they have short-period binary companions.
Spectral analysis of the quiescent low-mass X-ray binary in the globular cluster M30
Authors: Echiburú C S , Guillot S , Zhao Y , Heinke C O , Özel F , Webb N A
Published: May 2020

We present a recent Chandra observation of the quiescent low-mass X-ray binary containing a neutron star (NS), located in the globular cluster M30. We fit the thermal emission from the NS to extract its mass and radius. We find no evidence of flux variability between the two observations taken in 2001 and 2017, nor between individual 2017 observations, so we analyse them together to increase the signal-to-noise ratio. We perform simultaneous spectral fits using standard light-element composition atmosphere models (hydrogen or helium), including absorption by the interstellar medium, correction for pile-up of X-ray photons on the detector, and a power law for count excesses at high photon energy. Using a Markov chain Monte Carlo approach, we extract mass and radius credible intervals for both chemical compositions of the atmosphere: $\mbox{$R_{\rm NS}$}=7.94\mbox{{$\scriptstyle ^{ + 0.76}_{- 1.21}$}}$ km and $\mbox{$M_{\rm NS}$}\lt 1.19$ M⊙ assuming pure hydrogen, and $\mbox{$R_{\rm NS}$}=10.50\mbox{{$\scriptstyle ^{ + 2.88}_{- 2.03}$}}$ km and $\mbox{$M_{\rm NS}$}\lt 1.78$ M⊙ for helium, where the uncertainties represent the 90 per cent credible regions. For H, the small radius is difficult to reconcile with most current nuclear physics models (especially for nucleonic equations of state) and with other measurements of NS radii, with recent preferred values generally in the 11–14 km range. Whereas for He, the measured radius is consistent with this range. We discuss possible sources of systematic uncertainty that may result in an underestimation of the radius, identifying the presence of surface temperature inhomogeneities as the most relevant bias. According to this, we conclude that either the atmosphere is composed of He or it is anH atmosphere with a significant contribution of hotspots to the observed radiation.
Peter Pan discs: finding Neverland’s parameters
Authors: Coleman Gavin A L , Haworth Thomas J
Published: May 2020

Peter Pan discs are a recently discovered class of long-lived discs around low-mass stars that survive for an order of magnitude longer than typical discs. In this paper, we use disc evolutionary models to determine the required balance between initial conditions and the magnitude of dispersal processes for Peter Pan discs to be primordial. We find that we require low transport (α ∼ 10−4), extremely low external photoevaporation (${\le}10^{-9}\, {\rm M}_{\odot }\, {\rm yr^{-1}}$), and relatively high disc masses (>0.25M*) to produce discs with ages and accretion rates consistent with Peter Pan discs. Higher transport (α = 10−3) results in disc lifetimes that are too short and even lower transport (α = 10−5) leads to accretion rates smaller than those observed. The required external photoevaporation rates are so low that primordial Peter Pan discs will have formed in rare environments on the periphery of low-mass star-forming regions, or deeply embedded, and as such have never subsequently been exposed to higher amounts of UV radiation. Given that such an external photoevaporation scenario is rare, the required disc parameters and accretion properties may reflect the initial conditions and accretion rates of a much larger fraction of the discs around low-mass stars.
A memory of eS25 loss drives resistance phenotypes
Authors: Johnson Alex G , Flynn Ryan A , Lapointe Christopher P , Ooi Yaw Shin , Zhao Michael L , Richards Christopher M , Qiao Wenjie , Yamada Shizuka B , Couthouis Julien , Gitler Aaron D , Carette Jan E , Puglisi Joseph D
Published: May 2020

In order to maintain cellular protein homeostasis, ribosomes are safeguarded against dysregulation by myriad processes. Remarkably, many cell types can withstand genetic lesions of certain ribosomal protein genes, some of which are linked to diverse cellular phenotypes and human disease. Yet the direct and indirect consequences from these lesions are poorly understood. To address this knowledge gap, we studied in vitro and cellular consequences that follow genetic knockout of the ribosomal proteins RPS25 or RACK1 in a human cell line, as both proteins are implicated in direct translational control. Prompted by the unexpected detection of an off-target ribosome alteration in the RPS25 knockout, we closely interrogated cellular phenotypes. We found that multiple RPS25 knockout clones display viral- and toxin-resistance phenotypes that cannot be rescued by functional cDNA expression, suggesting that RPS25 loss elicits a cell state transition. We characterized this state and found that it underlies pleiotropic phenotypes and has a common rewiring of gene expression. Rescuing RPS25 expression by genomic locus repair failed to correct for the phenotypic and expression hysteresis. Our findings illustrate how the elasticity of cells to a ribosome perturbation can drive specific phenotypic outcomes that are indirectly linked to translation and suggests caution in the interpretation of ribosomal protein gene mutation data.
A universal method for the rapid isolation of all known classes of functional silencing small RNAs
Authors: Grentzinger Thomas , Oberlin Stefan , Schott Gregory , Handler Dominik , Svozil Julia , Barragan-Borrero Veronica , Humbert Adeline , Duharcourt Sandra , Brennecke Julius , Voinnet Olivier
Published: May 2020

Diverse classes of silencing small (s)RNAs operate via ARGONAUTE-family proteins within RNA-induced-silencing-complexes (RISCs). Here, we have streamlined various embodiments of a Q-sepharose-based RISC-purification method that relies on conserved biochemical properties of all ARGONAUTEs. We show, in multiple benchmarking assays, that the resulting 15-min benchtop extraction procedure allows simultaneous purification of all known classes of RISC-associated sRNAs without prior knowledge of the samples-intrinsic ARGONAUTE repertoires. Optimized under a user-friendly format, the method – coined ‘TraPR’ for Trans-kingdom, rapid, affordable Purification of RISCs – operates irrespectively of the organism, tissue, cell type or bio-fluid of interest, and scales to minute amounts of input material. The method is highly suited for direct profiling of silencing sRNAs, with TraPR-generated sequencing libraries outperforming those obtained via gold-standard procedures that require immunoprecipitations and/or lengthy polyacrylamide gel-selection. TraPR considerably improves the quality and consistency of silencing sRNA sample preparation including from notoriously difficult-to-handle tissues/bio-fluids such as starchy storage roots or mammalian plasma, and regardless of RNA contaminants or RNA degradation status of samples.
Novel Administration of Clofazimine for the Treatment of Mycobacterium avium Infection
Authors: Valinetz Ethan , Stankiewicz Karita Helen , Pottinger Paul S , Jain Rupali
Published: May 2020

Clofazimine has demonstrated in vitro activity against many nontuberculous mycobacteria. We present the case of a woman with cystic fibrosis who developed disseminated macrolide-resistant Mycobacterium avium infection following lung transplantation treated in part with clofazimine. We describe the novel administration of clofazimine via gastrostomy tube.
A virtuous circle? The effects of university–industry relationships in a region with low absorptive capacity
Authors: Vega-Jurado Jaider , Manjarrés-Henríquez Liney , Fernández-de-Lucio Ignacio , Naranjo-Africano Gloria
Published: May 2020

This article examines the effects of university–industry relationships (UIRs) in a Spanish region—Valencian Community—with low absorptive capacity. The analysis considers two effects of UIRs, one on business innovation and the other on the scientific production of academic researchers. The results reveal that UIRs have no significant effects on either firms’ technological innovation or academic scientific production. Therefore, these results suggest that, in territories with low absorptive capacity, UIRs, mainly R&D-based, do not produce the effects found in other contexts, which requires some rethinking about these types of territories.
Lysine (protein) requirements of lactating sows
Authors: Greiner Laura , Srichana Pariat , Usry James L , Neill Casey , Allee Gary L , Connor Joseph , Touchette Kevin J , Knight Christopher D
Published: May 2020

Five experiments were conducted to evaluate the lysine (Lys) requirements of lactating sows. All diets were formulated to be isocaloric 3.46 Mcal ME/kg and met or exceeded National Research Council recommendations. In all studies, sow feed intake, body weight loss/gain, subsequent reproduction, and litter growth rate (LGR) were evaluated. The data were analyzed as randomized complete block design using generalized linear model in SAS with parity as a block. Two hundred and sixty-four primiparous sows (PIC Camborough 22) were randomly allotted to one of five lactation treatments (total Lys of 0.95%, 1.05%, 1.15%, 1.25%, and 1.35%) in Exp. 1 from August 2005 through October 2005. As daily total dietary Lys intake increased from 52.10 to 77.53 g, piglet ADG and daily litter gain linearly improved (P < 0.01). From February 2007 through April 2007, 336 multiparous sows (parity 4 and older, PIC Camborough 29) were randomly allotted to one of five lactation treatments (total Lys 0.85%, 0.95%, 1.05%, 1.15%, or 1.25%) in Exp. 2. As dietary total Lys increased from 0.85% to 1.25% of the diet, there were no significant differences in litter performance, such as ADG, daily litter gain, and the number of pigs weaned. Experiment 3 was conducted from October 2008 through January 2009. Two hundred and seventy-nine primiparous gilts (PIC Camborough 29) were randomly allotted to one of five lactation treatments (total Lys 1.14%, 1.25%, 1.35%, 1.46%, and 1.57%). Actual total Lys intakes increased from 56.74 to 77.12 g/d. Feeding total dietary Lys quadratically decreased (P < 0.01) weaning-to-estrus interval and increased percentage bred by 10 d (P = 0.02). In Exp. 4, 200 sows (parity 4 and older, PIC Camborough 29) were randomly allotted to one of five treatments (0.85%, 0.95%, 1.05%, 1.15%, or 1.25% total Lys) from January 2008 through March 2008. As dietary total Lys increased from 42.40 to 66.15 g/d, sow body weight and LGRs were not influenced by dietary total Lys intakes. In Exp. 5, 324 parity 3 sows (PIC Camborough 29) were randomly allotted to one of five treatments (0.77%, 0.92%, 1.08%, 1.23%, and 1.38% total Lys) from August 2009 through October 2009. As daily dietary total Lys intake increased from 39.44 to 67.32 g, the percentage of sows bred by 10 d increased (P = 0.02), as well as the LGR. A broken-line quadratic regression analysis demonstrated that the total Lys requirement for LGR for parity 1 females is calculated as 72.68 − [6.04 × (3.55 − LGR)] and for parity 3+ females as 92.03 − [11.9 × (4.24 − LGR)].
Principles of Reinsurance Contract Law: The Reinsurer’s Perspective
Authors: Witthoff Eberhard
Published: May 2020

The global economic impact of reinsurance has increased significantly in recent years, leading to a desire for more certainty in the legal interpretation of reinsurance contracts as the number of disputes increases. Reinsurance contract wordings are not regulated by any overarching statutory law or regulations, in part due to the transnational nature of most reinsurance business. Additionally, reinsurance contracts have historically been interpreted by applying only general principles of contract law and good faith obligations with a heavy emphasis on the parties practice, usage and custom. This has led to significant uncertainty with respect to reinsurance disputes. The Principles of Reinsurance Contract Law (PRICL), published in 2019, aim to bring certainty to reinsurance contracts by improving wordings and developing widely accepted rules of interpretation.
An audit of uncertainty in multi-scale cardiac electrophysiology models
Authors: Clayton Richard H. , Aboelkassem Yasser , Cantwell Chris D. , Corrado Cesare , Delhaas Tammo , Huberts Wouter , Lei Chon Lok , Ni Haibo , Panfilov Alexander V. , Roney Caroline , dos Santos Rodrigo Weber
Published: May 2020

Models of electrical activation and recovery in cardiac cells and tissue have become valuable research tools, and are beginning to be used in safety-critical applications including guidance for clinical procedures and for drug safety assessment. As a consequence, there is an urgent need for a more detailed and quantitative understanding of the ways that uncertainty and variability influence model predictions. In this paper, we review the sources of uncertainty in these models at different spatial scales, discuss how uncertainties are communicated across scales, and begin to assess their relative importance. We conclude by highlighting important challenges that continue to face the cardiac modelling community, identifying open questions, and making recommendations for future studies.

This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Personalization of electro-mechanical models of the pressure-overloaded left ventricle: fitting of Windkessel-type afterload models
Authors: Marx Laura , Gsell Matthias A. F. , Rund Armin , Caforio Federica , Prassl Anton J. , Toth-Gayor Gabor , Kuehne Titus , Augustin Christoph M. , Plank Gernot
Published: May 2020

Computer models of left ventricular (LV) electro-mechanics (EM) show promise as a tool for assessing the impact of increased afterload upon LV performance. However, the identification of unique afterload model parameters and the personalization of EM LV models remains challenging due to significant clinical input uncertainties. Here, we personalized a virtual cohort of
N
 = 17 EM LV models under pressure overload conditions. A global–local optimizer was developed to uniquely identify parameters of a three-element Windkessel (Wk3) afterload model. The sensitivity of Wk3 parameters to input uncertainty and of the EM LV model to Wk3 parameter uncertainty was analysed. The optimizer uniquely identified Wk3 parameters, and outputs of the personalized EM LV models showed close agreement with clinical data in all cases. Sensitivity analysis revealed a strong dependence of Wk3 parameters on input uncertainty. However, this had limited impact on outputs of EM LV models. A unique identification of Wk3 parameters from clinical data appears feasible, but it is sensitive to input uncertainty, thus depending on accurate invasive measurements. By contrast, the EM LV model outputs were less sensitive, with errors of less than 8.14% for input data errors of 10%, which is within the bounds of clinical data uncertainty.

This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments
Authors: Lei Chon Lok , Clerx Michael , Whittaker Dominic G. , Gavaghan David J. , de Boer Teun P. , Mirams Gary R.
Published: May 2020

Mathematical models of ion channels, which constitute indispensable components of action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study, we fitted cell-specific models to hERG1a (Kv11.1) recordings simultaneously measured using an automated high-throughput system, and studied cell-cell variability by inspecting the resulting model parameters. However, the origin of the observed variability was not identified. Here, we study the source of variability by constructing a model that describes not just ion current dynamics, but the entire voltage-clamp experiment. The experimental artefact components of the model include: series resistance, membrane and pipette capacitance, voltage offsets, imperfect compensations made by the amplifier for these phenomena, and leak current. In this model, variability in the observations can be explained by either cell properties, measurement artefacts, or both. Remarkably, by assuming that variability arises exclusively from measurement artefacts, it is possible to explain a larger amount of the observed variability than when assuming cell-specific ion current kinetics. This assumption also leads to a smaller number of model parameters. This result suggests that most of the observed variability in patch-clamp data measured under the same conditions is caused by experimental artefacts, and hence can be compensated for in post-processing by using our model for the patch-clamp experiment. This study has implications for the question of the extent to which cell-cell variability in ion channel kinetics exists, and opens up routes for better correction of artefacts in patch-clamp data.

This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.
Influence of countries adopted policies for COVID-19 reduction under the view of the airborne transmission framework
Authors: Telles Charles Roberto
Published: May 2020

Daily new cases dataset since January 2020 were used to search for evidences of SARS-CoV-2 community transmission as the main nowadays cause of constant infection rates among countries. Despite traditional forms of transmission of this virus (droplets and aerosols in medical facilities), new evidence suggests aerosols forming patterns in the atmosphere as a main factor of community transmission outside medical spaces. Following these findings, this research focused on comparing some countries and the adopted policy used as preventive framework for virus community transmission. Countries social distancing policy aspect, of one to two meters of physical distance, was statistically analyzed from January to early May 2020, and countries were divided into those implementing only social physical distance and those implementing distancing with additional transmission isolation (with masks and city disinfection). Correlating countries social distancing policy adoption with other preventive measures such as social isolation and COVID-19 testing, a new indicator results, derived from SIR models and Weibull parameterization, show that only social physical distance measure could act as a factor for SARS-CoV-2 transmission with respect to atmosphere carrier potential. In this sense, the type of social distancing framework adopted by some countries without additional measures might represent a main model for the constant reproductive spread patterns of SARS-CoV-2 within the community transmission. Finally, the findings have important implications for the policy making to be adopted globally as well as individual-scale preventive methods.
Occupational Exposures to Blood and Body Fluids among Healthcare Workers in Ethiopia: A Systematic Review and Meta-Analysis
Authors: Sahiledengle Biniyam , Tekalegn Yohannes , Woldeyohannes Demelash , Edward Quisido Bruce John
Published: May 2020

Background: Occupational exposure to blood and body fluids is a major risk factor for the transmission of blood-borne infections to healthcare workers. There are several primary studies in Ethiopia yet they might not be at the national level to quantify the extent of occupational blood and body fluid exposures among the healthcare workers. This systematic review and meta-analysis aimed to estimate the pooled prevalence of occupational blood and body fluid exposure of health-care workers in Ethiopia.

Methods: PubMed, Science Direct, Hinari, Google Scholar, and the Cochrane library were systematically searched; withal, the references of appended articles were also checked for further possible sources. The Cochrane Q test statistics and I2 tests were used to assess the heterogeneity of the included studies. A random-effects meta-analysis model was used to estimate the lifetime and 12-month prevalence of occupational exposure to blood and body fluids among health-care workers in Ethiopia.

Results: Of the 641 articles identified through the database search, 37 studies were included in the final analysis. The estimated pooled lifetime and 12-month prevalence on occupational exposure to blood and body fluids among healthcare workers were found to be at 54.15% (95% confidence interval (CI): 47.54,60.75) and 44.24% (95%CI: 36.98,51.51), respectively. The study identified a variation in healthcare workers whom were exposed to blood and body fluids across Ethiopian regions.

Conclusion: The finding of the present study revealed that there was a high level of annual and lifetime exposures to blood and body fluids among the healthcare workers of Ethiopia.
Machine Learning for Interpretation of DNA Variants of Maturity-Onset Diabetes of the Young Genes Based on ACMG Criteria
Authors: Liu Yichuan , Qu Huiqi , Wenocur Adam S , Qu Jingchun , Chang Xiao , Glessner Joseph , Sleiman Patrick , Tian Lifeng , Hakonarson Hakon
Published: May 2020

Background: Maturity-onset diabetes of the young (MODY) is a group of dominantly inherited monogenic diabetes, with HNF4A-MODY, GCK-MODY and HNF1A-MODY being the three most common genes responsible. Molecular diagnosis of MODY is important for precise treatment. While a DNA variant causing MODY can be assessed by the criteria of the American College of Medical Genetics and Genomics (ACMG) guidelines, gene-specific assessment of disease-causing mutations is important to differentiate between the MODY subtypes. As the ACMG criteria were not originally designed for machine learning algorithms, they are not true independent variables.
Methods: In this study, we applied machine learning models for interpretation of DNA variants in MODY genes defined by the ACMG criteria based on Human Gene Mutation Database (HGMD) and ClinVar.
Results: The results show highly predictive abilities with accuracy over 95%, suggest that this model could serve as a fast, gene-specific method for physicians or genetic counselors assisting with diagnosis and reporting, especially when confronted by contradictory ACMG criteria. Also, the weight of the ACMG criteria shows gene specificity which advocates for the application of machine learning methods with the ACMG criteria to capture the most relevant information for each disease-related variant.
Conclusion: Our results highlight the need for different weights of the ACMG criteria in relation with different MODY genes for accurate functional classification. For proof of principle, we applied the ACMG criteria as feature vectors in a machine learning model obtaining precision-based result.
A new method to triage colorectal cancer referrals in the UK using serum Raman spectroscopy and machine learning
Authors: Jenkins Cerys A , Chandler Susan , Jenkins Rhys , Thorne Kym , Woods Freya , Cunningham Andrew , Nelson Kayleigh , Still Rachel , Walters Jenna , Gywnne Non , Chea Wilson , Harford Rachel , O'Neill Claire , Hepburn Julie , Hill Ian , Wilkes Heather , Fegan Greg , Dunstan Peter , Harris Dean A
Published: May 2020

Suspected colorectal cancer (CRC) referrals based on non-specific symptoms currently lead to large numbers of patients being referred for invasive investigations and poor yield in cancer detection. Secondary care diagnostics, particularly endoscopy, struggle to meet the ever-increasing demand and patients face lengthy waits from the point of referral. Here we propose a blood test utilising high-throughput Raman spectroscopy and machine learning as an accurate triage tool. We present results from the first mixed methods clinical validation study of its kind, evaluating the ability of the test to perform in its target population of primary care patients, and its acceptability to those administering and receiving the test. The test was able to accurately rule out cancer with a negative predictive value of 98.0%. This performance could reduce the number of invasive diagnostic procedures in the cohort by at least 47%. Collectively, our findings promote a novel, non-invasive solution to triage CRC referrals with potential to reduce patient anxiety, accelerate access to treatment and improve outcomes.
The Polygenic Score Catalog: an open database for reproducibility and systematic evaluation
Authors: Lambert Samuel A , Gil Laurent , Jupp Simon , Ritchie Scott C , Xu Yu , Buniello Annalisa , Abraham Gad , Chapman Michael , Parkinson Helen , Danesh John , MacArthur Jacqueline A , Inouye Michael
Published: May 2020

Polygenic [risk] scores (PGS) can enhance prediction and understanding of common diseases and traits. However, the reproducibility of PGS and their subsequent applications in biological and clinical research have been hindered by several factors, including: inadequate and incomplete reporting of PGS development, heterogeneity in evaluation techniques, and inconsistent access to, and distribution of, the information necessary to calculate the scores themselves. To address this we present the PGS Catalog (www.PGSCatalog.org), an open resource for polygenic scores. The PGS Catalog currently contains 192 published PGS from 78 publications for 86 diverse traits, including diabetes, cardiovascular diseases, neurological disorders, cancers, as well as traits like BMI and blood lipids. Each PGS is annotated with metadata required for reproducibility as well as accurate application in independent studies. Using the PGS Catalog, we demonstrate that multiple PGS can be systematically evaluated to generate comparable performance metrics. The PGS Catalog has capabilities for user deposition, expert curation and programmatic access, thus providing the community with an open platform for polygenic score research and translation.
Liver Function in Novel Coronavirus Disease (COVID-19): A Systematic Review and Meta-Analysis
Authors: Zahedi Mohammad , Yousefi Mohammad , Abounoori Mahdi , Malekan Mohammad , Tajik Fatemeh , Heydari Keyvan , Mortazavi Parham , Ghazaeian Monireh , Sheydaee Fateme , Nasirzadeh Amirreza , Alizadeh-Navaei Reza
Published: May 2020

Introduction:The outbreak of new coronavirus has become a global public health challenge. Given a consequential liver function, and the high risk of death coming from liver disorders, the assessment of Novel Coronavirus Disease on liver function is importance. Hence, we carried out this meta-analysis to heightening insight into the occult features of COVID 19, which is likely to affect liver function.
Method:This study was performed using databases of Web of Science, Scopus, and PubMed. We considered English cross-sectional and case-series papers, which reported available findings on the association between liver injury and COVID-19 infection. We used the STATA v.11 and random effect model for data analysis.
Result:In this present meta-analysis, 52 papers, including 8,463 COVID-19 patients, were studied. The prevalence of increased liver enzymes among the patients, including Alanine aminotransferase, Aspartate aminotransferase, were 30% and 21% in non-severe patients, respectively, which were 38% and 48% in severe patients. The prevalence of increasing C-reactive protein, Lactate dehydrogenase, D-dimer, and Bilirubin were 55%, 39%, 28%, and 10% in non-severe patients respectively, which were 78%, 75%, 79% and 17% in sever patients.The prevalence of liver toxicity as a complication of COVID-19 was 20%.Also patients who have severe condition are 5.54, 4.22, 4.96, 4.13 and 4.34 times more likely to have elevated CRP, ALT, AST, LDH, D-dimer enzymes retrospectively.
Conclusion:Elevation of some liver markers were higher in patients with severe COVID-19 infection. All to gather, we assumed that abnormal liver markers could act as a prognostic factor for a better survey of COVID-19.
A Systematic Review and Meta-analysis of Therapeutic options against SARS-CoV-2
Authors: Thoguluva Chandrasekar Viveksandeep , Venkatesalu Bhanuprasad , Patel Harsh K , Spadaccini Marco , Manteuffel Jacob , Ramesh Mayur S
Published: May 2020

Importance
Treatment options for Severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) are limited with no clarity on the efficacy and safety profiles.
Objective
To assess if the effect estimate of any intervention improves the outcomes and safety profile.
Data sources
PubMed, Embase, Cochrane Central were searched from December 1, 2019 to May 11, 2020.
Study selection
Any prospective/retrospective clinical study on SARS-CoV-2 patients above 18 years of age with report on therapeutic interventions.
Data synthesis and extraction
Data was screened and extracted by two independent investigators.
Main outcomes and measures
The primary outcome was all-cause in-hospital mortality. The secondary outcomes were rates of mechanical ventilation, viral clearance, adverse events, discharge, progression to severe disease, median time for clinical recovery and anti-viral clearance. Pooled rates and odds ratios (OR) were calculated.
Results
A total of 29 studies with 5207 participants were included in the analysis. The pooled all-cause in-hospital mortality rate was 12.8% (95%CI: 8.1%-17.4%) in intervention arm. There was no significant difference in mortality between both arms overall (OR: 1.36, 95% CI: 0.97-1.89). The mortality was significantly higher in the Hydroxychloroquine (HCQ) group compared to control: (1.86, 95% CI: 1.38-2.50). The need for mechanical ventilation in patients with mild-moderate disease was 13.5% vs 9.8% in intervention and control groups, with no significant difference (OR: 1.58, 95% CI: 0.60-4.15).The median duration for viral clearance in the intervention arm was 6.1 (IQR: 4.3-8.8) days and control arm was 9 (IQR: 4.5-14) days, with no significant difference between the groups (p = 0.37). There was no significant difference between pooled adverse event rates in intervention and control groups: 34% vs 29.5% (OR: 1.44, 95% CI: 0.70-2.94), respectively. However, incidence of adverse events was significantly higher in HCQ sub-group (OR: 3.88, 95% CI: 1.60-9.45, I2 = 0%). There was no significant difference in other secondary outcomes.
Conclusion and relevance
The use of hydroxychloroquine was associated with increased mortality and adverse event rates. No other therapeutic intervention including Lopinavir/Ritonavir, Remdesivir or Tocilizumab seem to alter the natural course of the disease. There is a further need for well-designed randomized clinical trials.
Seminal plasma exosomes evoke calcium signals via the CatSper channel to regulate human sperm function
Authors: Zhang Xiaoning , Song Dandan , Kang Hang , Zhou Wenwen , Chen Houyang , Zeng Xuhui
Published: May 2020

Seminal plasma exosomes (SPE) have been proposed to regulate intracellular calcium concentration ([Ca2+]i) and sperm function. However, neither the underlying mechanisms by which [Ca2+]i is regulated by SPE nor the physiological and pathological significance of the SPE-evoked calcium signal are fully understood. Here, we successfully isolated and characterized SPE by several methods, including transmission electron microscopy, nanoparticle tracking and nanoflow cytometry analysis. Application of SPE dose-dependently increased human sperm [Ca2+]i via extracellular Ca2+influx. The Ca2+influx was mediated by the sperm-specific CatSper channel, because the SPE-elevated [Ca2+]i was suppressed by a CatSper inhibitor, and SPE potentiated the CatSper current in human sperm. The role of CatSper in the SPE-induced elevation of [Ca2+]i was further confirmed by the absence of the SPE-induced [Ca2+]i increase and CatSper current in a CatSper-deficient sample. Furthermore, both protein and no-protein components in SPE were shown to contribute to the elevated [Ca2+]i, as well as the hyperactivated motility of human sperm. Interestingly, when sperm were stimulated with exosomes derived from asthenozoospermic semen, the elevation of [Ca2+]i was significantly lower than that by exosomes isolated from normal seminal plasma. The SPE from normal seminal plasma improved the motility of sperm from asthenozoospermic samples. Taken together, these findings demonstrated that SPE modulates Ca2+signaling and human sperm function by activating a CatSper channel. The application of SPE to enhance sperm motility may provide a new clinical avenue for asthenozoospermic men.