bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensitivity in Detection of Antibodies to Nucleocapsid and Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Coronavirus Disease 2019
Authors: Burbelo Peter D , Riedo Francis X , Morishima Chihiro , Rawlings Stephen , Smith Davey , Das Sanchita , Strich Jeffrey R , Chertow Daniel S , Davey Richard T , Cohen Jeffrey I
Published: May 2020

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is associated with respiratory-related disease and death. Assays to detect virus-specific antibodies are important to understand the prevalence of infection and the course of the immune response.

Methods

Quantitative measurements of plasma or serum antibodies to the nucleocapsid and spike proteins were analyzed using luciferase immunoprecipitation system assays in 100 cross-sectional or longitudinal samples from patients with SARS-CoV-2 infection. A subset of samples was tested both with and without heat inactivation.

Results

At >14 days after symptom onset, antibodies against SARS-CoV-2 nucleocapsid protein showed 100% sensitivity and 100% specificity, whereas antibodies to spike protein were detected with 91% sensitivity and 100% specificity. Neither antibody levels nor the rate of seropositivity were significantly reduced by heat inactivation of samples. Analysis of daily samples from 6 patients with COVID-19 showed anti-nucleocapsid and spike protein antibodies appearing between days 8 and 14 after initial symptoms. Immunocompromised patients generally had a delayed antibody response to SARS-CoV-2, compared with immunocompetent patients.

Conclusions

Antibody to the nucleocapsid protein of SARS-CoV-2 is more sensitive than spike protein antibody for detecting early infection. Analyzing heat-inactivated samples with a luciferase immunoprecipitation system assay is a safe and sensitive method for detecting SARS-CoV-2 antibodies.
Enhancing network activation in natural killer cells: predictions from in silico modeling
Authors: Makaryan Sahak Z , Finley Stacey D
Published: May 2020

Natural killer (NK) cells are part of the innate immune system and are capable of killing diseased cells. As a result, NK cells are being used for adoptive cell therapies for cancer patients. The activation of NK cell stimulatory receptors leads to a cascade of intracellular phosphorylation reactions, which activates key signaling species that facilitate the secretion of cytolytic molecules required for cell killing. Strategies that maximize the activation of such intracellular species can increase the likelihood of NK cell killing upon contact with a cancer cell and thereby improve efficacy of NK cell-based therapies. However, due to the complexity of intracellular signaling, it is difficult to deduce a priori which strategies can enhance species activation. Therefore, we constructed a mechanistic model of the CD16, 2B4 and NKG2D signaling pathways in NK cells to simulate strategies that enhance signaling. The model predictions were fit to published data and validated with a separate dataset. Model simulations demonstrate strong network activation when the CD16 pathway is stimulated. The magnitude of species activation is most sensitive to the receptor’s initial concentration and the rate at which the receptor is activated. Co-stimulation of CD16 and NKG2D in silico required fewer ligands to achieve half-maximal activation than other combinations, suggesting co-stimulating these pathways is most effective in activating the species. We applied the model to predict the effects of perturbing the signaling network and found two strategies that can potently enhance network activation. When the availability of ligands is low, it is more influential to engineer NK cell receptors that are resistant to proteolytic cleavage. In contrast, for high ligand concentrations, inhibiting phosphatase activity leads to sustained species activation. The work presented here establishes a framework for understanding the complex, nonlinear aspects of NK cell signaling and provides detailed strategies for enhancing NK cell activation.
Lung fibroblasts produce IL-33 in response to stimulation with retinoblastoma-binding protein 9 via production of prostaglandin E2
Authors: Adachi Takumi , Yasuda Koubun , Muto Taichiro , Serada Satoshi , Yoshimoto Tomohiro , Ishii Ken J , Kuroda Etsushi , Araki Kimi , Ohmuraya Masaki , Naka Tetsuji , Nakanishi Kenji
Published: May 2020

Intestinal nematode infection induces pulmonary eosinophilia via IL-33, although the mechanism of pulmonary IL-33 induction remains unclear. Because nematode migration damages lungs, we speculated that lung-derived damage-associated molecular patterns (DAMPs) possess an IL-33-inducing activity (IL33ia). Indeed, intra-nasal administration of a lung extract induced IL-33 production in lungs. Additionally, lung extracts increased Il33 mRNA expression in primary lung fibroblasts. Proteomic analysis identified retinoblastoma-binding protein 9 (RBBP9) as a major DAMP with IL33ia. RBBP9 was originally discovered as a protein that provides cells with resistance to the growth inhibitory effect of transforming growth factor (TGF)-β1. Here, we found that stimulation by RBBP9 induced primary fibroblasts to produce prostaglandin E2 (PGE2) that, in turn, induced fibroblasts to produce IL-33. RBBP9-activated fibroblasts expressed mRNAs of cyclooxygenase-2 (COX-2) and PGE2 synthase-1 that convert arachidonic acid to PGE2. Furthermore, they expressed PGE2 receptors E-prostanoid (EP) 2 and EP4. Thus, treatment with a COX-2 inhibitor or EP2 and/or EP4 receptor antagonists inhibited RBBP9-induced IL-33 production. Nematode infection induced pulmonary Il33 mRNA expression, which was inhibited by the COX-2 inhibitor or EP2 and EP4 antagonists, suggesting that nematode infection induced pulmonary Il33 mRNA via PGE2. RBBP9 was expressed constitutively in the lung in the steady state, which did not increase after nematode infection. Finally, we found that Rbbp9-deficient mice had a significantly diminished capacity to increase pulmonary Il33 mRNA expression following nematode infection. Thus, the PGE2-EP2/EP4 pathway activated by RBBP9 released from damaged lungs is important for pulmonary IL-33 production in nematode-infected animals.
Barriers to hospital electronic public health reporting and implications for the COVID-19 pandemic
Authors: Holmgren A Jay , Apathy Nate C , Adler-Milstein Julia
Published: May 2020

We sought to identify barriers to hospital reporting of electronic surveillance data to local, state, and federal public health agencies and the impact on areas projected to be overwhelmed by the COVID-19 pandemic. Using 2018 American Hospital Association data, we identified barriers to surveillance data reporting and combined this with data on the projected impact of the COVID-19 pandemic on hospital capacity at the hospital referral region level.

Our results find the most common barrier was public health agencies lacked the capacity to electronically receive data, with 41.2% of all hospitals reporting it. We also identified 31 hospital referral regions in the top quartile of projected bed capacity needed for COVID-19 patients in which over half of hospitals in the area reported that the relevant public health agency was unable to receive electronic data.

Public health agencies’ inability to receive electronic data is the most prominent hospital-reported barrier to effective syndromic surveillance. This reflects the policy commitment of investing in information technology for hospitals without a concomitant investment in IT infrastructure for state and local public health agencies.
Chronic prenatal heat stress alters growth, carcass composition, and physiological response of growing pigs subjected to postnatal heat stress
Authors: Serviento Aira Maye , Lebret Bénédicte , Renaudeau David
Published: May 2020

Postnatal heat stress (HS) effects on pig physiology and performance are widely studied but prenatal HS studies, albeit increasing, are still limited. The objective of this study was to evaluate the chronic prenatal HS effects in growing pigs raised in postnatal thermoneutral (TN) or in HS environment. For prenatal environment (PE), mixed-parity pregnant sows were exposed to either TN (PTN; cyclic 18 to 24 °C; n = 12) or HS (PHS; cyclic 28 to 34 °C; n = 12) conditions from day 9 to 109 of gestation. Two female offspring per sow were selected at 10 wk of age and allotted to one of two postnatal growing environments (GE): GTN (cyclic 18 to 24 °C; n = 24) and GHS (cyclic 28 to 34 °C; n = 24). From 75 to 140 d of age, GTN pigs remained in GTN conditions, while GHS pigs were in GTN conditions from 75 to 81 d of age and in GHS conditions from 82 to 140 d of age. Regardless of PE, postnatal HS increased rectal and skin temperatures (+0.30 and +1.61 °C on average, respectively; P < 0.01) and decreased ADFI (−332 g/d; P < 0.01), resulting in lower ADG and final BW (−127 g/d and −7.9 kg, respectively; P < 0.01). The GHS pigs exhibited thicker backfat (P < 0.01), lower carcass loin percentage (P < 0.01), increased plasma creatinine levels (P < 0.01), and decreased plasma glucose, nonesterified fatty acids, T3, and T4 levels (P < 0.05). Prenatal HS increased feed intake in an age-dependent manner (+10 g·kg BW–0.60·d−1 for PHS pigs in the last 2 wk of the trial; P = 0.02) but did not influence BW gain (P > 0.10). Prenatal HS decreased the plasma levels of superoxide dismutase on day 3 of GHS (trend at P = 0.08) and of T4 on day 49 (P < 0.01) but did not affect T3 on day 3 nor 49 (P > 0.10). Prenatal HS increased rectal and skin temperatures and decreased temperature gradient between rectal and skin temperatures in GTN pigs (+0.10, +0.33 and −0.22 °C, respectively; P < 0.05) but not in GHS pigs (P > 0.10). There were also PE × GE interactions found with lower BW (P = 0.06) and higher backfat (P < 0.01) and perirenal adiposity (P < 0.05) for GHS–PHS pigs than the other groups. Overall, increased body temperature and altered thyroid functions and physiological stress responses suggest decreased heat tolerance and dissipation ability of pigs submitted to a whole-gestation chronic prenatal HS. Postnatal HS decreased growth performance, increased carcass adiposity, and affected metabolic traits and thyroid functions especially in pigs previously submitted to prenatal HS.
Beef cattle responses to pre-grazing sward height and low level of energy supplementation on tropical pastures
Authors: Dórea João R R , Gouvêa Vinícius N , Agostinho Neto Luiz Roberto D , Da Silva Sila C , Brink Geoffrey E , Pires Alexandre V , Santos Flávio A P
Published: May 2020

The objective of this study was to investigate the effects of energy supplementation and pre-grazing sward height on grazing behavior, nutrient intake, digestion, and metabolism of cattle in tropical pastures managed as a rotational grazing system. Eight rumen-cannulated Nellore steers (24 mo of age; 300 ± 6.0 kg body weight [BW]) were used in a replicated 4 × 4 Latin square design. Treatments consisted of two levels of energy supplementation (0% [none] or 0.3% of BW of ground corn on an as-fed basis) and two pre-grazing sward heights (25 cm [defined by 95% light interception (LI)] or 35 cm [defined by ≥ 97.5% LI]) constituting four treatments. Steers grazed Marandu Palisadegrass [Brachiaria brizantha Stapf. cv. Marandu] and post-grazing sward height was 15 cm for all treatments. Forage dry matter intake (DMI) was increased (P = 0.01) when sward height was 25 cm (1.86% vs. 1.32% BW) and decreased (P = 0.04) when 0.3% BW supplement was fed (1.79% vs. 1.38% BW). Total and digestible DMI were not affected by energy supplementation (P = 0.57) but were increased when sward height was 25 cm (P = 0.01). Steers grazing the 25-cm sward height treatment spent less time grazing and more time resting, took fewer steps between feeding stations, and had a greater bite rate compared with 35-cm height treatment (P < 0.05). Energy supplementation reduced grazing time (P = 0.02) but did not affect any other grazing behavior parameter (P = 0.11). Energy supplementation increased (P < 0.01) diet dry matter digestibility but had no effect on crude protein and neutral detergent fiber digestibilities (P = 0.13). Compared with 35-cm pre-grazing sward height, steers at 25 cm presented lower rumen pH (6.39 vs. 6.52) and greater rumen ammonia nitrogen (11.22 vs. 9.77 mg/dL) and N retention (49.7% vs. 20.8%, P < 0.05). The pre-grazing sward height of 25 cm improved harvesting efficiency and energy intake by cattle, while feeding 0.3% of BW energy supplement did not increase the energy intake of cattle on tropical pasture under rotational grazing.
Ruminal microbes of adult sheep do not degrade extracellular l-citrulline
Authors: Gilbreath Kyler R , Bazer Fuller W , Satterfield M Carey , Cleere Jason J , Wu Guoyao
Published: May 2020

This study determined whether extracellular citrulline is degraded by ruminal bacteria of sheep. In the first experiment, whole rumen fluid (3 mL) from six adult Suffolk sheep was incubated at 37 °C with 5 mM l-glutamine (Gln), l-glutamate (Glu), l-arginine (Arg), or l-citrulline (Cit) for 0, 0.5, 1, and 2 h or with 0, 0.5, 2, or 5 mM Gln, Glu, Arg, or Cit for 2 h. An aliquot (50 µL) of the incubation solution was collected at the predetermined time points for amino acids (AA) analyses. Results showed extensive hydrolysis of Gln into Glu and ammonia, of Arg into l-ornithine and l-proline, but little or no degradation of extracellular Cit or Glu by ruminal microbes. In the second experiment, six adult Suffolk sheep were individually fed each of three separate supplements (8 g Gln , Cit, or urea) on three separate days along with regular feed (800 g/animal). Blood (2 mL) was sampled from the jugular vein prior to feeding (time 0) and at 0.5, 1, 2, and 4 h after consuming the supplement. Plasma was analyzed for AA, glucose, ammonia, and urea. The concentrations of Cit in the plasma of sheep consuming this AA increased (P < 0.001) by 117% at 4 h and those of Arg increased by 23% at 4 h, compared with the baseline values. Urea or Gln feeding did not affect (P > 0.05) the concentrations of Cit or Arg in plasma. These results indicate that Cit is not metabolized by ruminal microbes of sheep and is, therefore, absorbed as such by the small intestine and used for the synthesis of Arg by extrahepatic tissues.
Coarse, Efficient Decision-Making
Authors: Mandler Michael
Published: May 2020

To minimize the cost of making decisions, an agent should use criteria to sort alternatives and each criterion should sort coarsely. To decide on a movie, for example, an agent could use one criterion that orders movies by genre categories, another by director categories, and so on, with a small number of categories in each case. The agent then needs to aggregate the criterion orderings, possibly by a weighted vote, to arrive at choices. As criteria become coarser (each criterion has fewer categories) decision-making costs fall, even though an agent must then use more criteria. The most efficient option is consequently to select the binary criteria with two categories each. This result holds even when the marginal cost of using additional categories diminishes to 0. The extensive use of coarse criteria in practice may therefore be a result of optimization rather than cognitive limitations. Binary criteria also generate choice functions that maximize rational preferences: decision-making efficiency implies rational choice.
International Politics in the Age of Existential Threats
Authors: Sears Nathan Alexander
Published: May 2020

Humans in the twenty-first century live under the specter of anthropogenic existential threats to human civilization and survival. What is the significance of humanity’s capacity for self-destruction to the meaning of “security” and “survival” in international politics? The argument is that it constitutes a material “revolution” in international politics—that is, the growing spectrum of anthropogenic existential threats represents a radical transformation in the material context of international politics that turns established truths about security and survival on their heads. The paper develops a theoretical framework based in historical security materialism, especially the theoretical proposition that the material circumstances of the “forces of destruction” determine the security viability of different “modes of protection”, political “units” and “structures”, and “security ideologies” in international politics. The argument seeks to demonstrate the growing disjuncture (or “contradiction”) between the material context of anthropogenic existential threats (“forces of destruction”); and the security practices of war, the use of military force, and the balance-of-power (“modes of protection”); the political units of nation-states and structure of international anarchy (“political superstructure”); and the primacy of “national security” and doctrines of “self-help” and “power politics” in international politics (“security ideologies”). Specifically, humanityapos;s survival interdependence with respect to anthropogenic existential threats calls into question the centrality of national security and survival in international politics. In an age of existential threats, “security” is better understood as about the survival of humanity.
Colonic diverticulitis following open-heart surgery: a case report of an unusual postoperative gastrointestinal complication
Authors: Acheampong Derrick , Boateng Percy
Published: May 2020

Diverticulitis, though a common gastrointestinal disease, is rare following open-heart surgery. There is insufficient data regarding its incidence and management post-cardiac surgery. Especially in patients with atypical presentation, diagnosis and management can be challenging. This case outlines one such atypical diverticulitis case in which a 57-year-old female patient developed perforated diverticulitis with pelvic abscess accumulation following left ventricular aneurysm (LVA) repair. Diagnosis, appropriate management and treatment approaches are discussed. Cardiac surgeons should consider the possibility of diverticulitis in patients reporting nonspecific abdominal pain following cardiac surgery to ensure early diagnosis and institution of appropriate treatment to prevent associated adverse outcomes.
Reobserving the NLS1 galaxy RE J1034+396 – I. The long-term, recurrent X-ray QPO with a high significance
Authors: Jin Chichuan , Done Chris , Ward Martin
Published: May 2020

RE J1034+396 is a narrow-line Seyfert 1 galaxy (NLS1) in which the first significant X-ray quasi-periodic oscillation (QPO) in an active galactic nucleus (AGN) was observed in 2007. We report the detection of this QPO in a recent XMM–Newton observation in 2018 with an even higher significance. The quality factor of this QPO is 20, and its period is 3550 ± 80 s, which is 250 ± 100 s shorter than in 2007. While the QPO’s period has no significant energy dependence, its fractional root mean square variability increases from 4 per cent in 0.3–1 keV to 12 per cent in 1–4 keV bands. An interesting phenomenon is that the QPO in 0.3–1 keV leads that in the 1–4 keV bands by 430 ± 50 s with a high coherence, opposite to the soft X-ray lag reported for the observation in 2007. We speculate that the QPO has an intrinsic hard lag, while the previous reported soft lag is caused by the interference of stochastic variability. This soft X-ray lead in the new data supports the idea that the QPO of RE J1034+396 is a possible AGN counterpart of the 67 Hz high-frequency QPO seen in the black hole binary GRS 1915+105. We also search for QPO harmonics, but do not find any significant signals. Our new data reinforce previous results that the QPO is seen in a specific spectral state, as the only two observations showing no significant QPO signal exhibit an even stronger soft X-ray excess than the other six observations that display the QPO. Therefore, our results imply that the QPO in RE J1034+396 is physically linked to a soft X-ray component.
Photometric study of the young open clusters IC 1442, King 21, and Trumpler 7
Authors: Maurya Jayanand , Joshi Y C , Gour A S
Published: May 2020

We carried out the UBVRcIc photometric study of three poorly studied young open clusters IC 1442, King 21, and Trumpler 7 (Tr 7). We obtained 263, 244, and 128 member stars using Gaia Data Release 2 proper motions and parallaxes in IC 1442, King 21, and Tr 7, respectively. The reddening, E(B − V), was derived to be 0.54 ± 0.04, 0.76 ± 0.06, and 0.38 ± 0.04 mag for these clusters. The comparison of observed colour–magnitude diagrams with solar metallicity isochrones yields log(age) = 7.40 ± 0.30, 7.70 ± 0.20, and 7.85 ± 0.25 yr and corresponding distances of 2847 ± 238, 2622 ± 156, and 1561 ± 74 pc for IC 1442, King 21, and Tr 7, respectively. The estimated mass function (MF) slopes are found to be −1.94 ± 0.18, −1.54 ± 0.32, and −2.31 ± 0.29 for IC 1442, King 21, and Tr 7, respectively. The study of MF slopes done separately in the inner and the outer regions of these clusters gives a steeper slope in the outer region, which suggests spatial variation in slope and mass segregation in the clusters. We found evidence of mass segregation after the dynamical study in these clusters. The obtained relaxation time, TE, is 74, 26, and 34 Myr for the clusters IC 1442, King 21, and Tr 7, respectively. The mass segregation in IC 1442 may be caused by early dynamical relaxation. The estimated TE is well below the ages of King 21 and Tr 7, which indicates that these clusters are dynamically relaxed.
Calibration requirements for epoch of reionization 21-cm signal observations – I. Effect of time-correlated gains
Authors: Kumar Jais , Dutta Prasun , Roy Nirupam
Published: May 2020

The residual gain errors add to the systematics of the radio interferometric observations. In case of the high dynamic range observations, these systematic effects dominates over the thermal noise of the observation. In this work, we investigate the effect of time-correlated residual gain errors in the estimation of the power spectrum of the sky brightness distribution in high dynamic range observations. Particularly, we discuss a methodology to estimate the bias in the power spectrum estimator of the redshifted 21-cm signal from neutral hydrogen in the presence of bright extragalactic compact sources. We find, that for the visibility-based power spectrum estimators, particularly those use nearby baseline correlations to avoid noise bias, the bias in the power spectrum arises mainly from the time correlation in the residual gain error. The bias also depends on the baseline distribution for a particular observation. Analytical calculations show that the bias is dominant for certain types of baseline pairs used for the visibility correlation. We perform simulated observation of extragalactic compact sources in the presence of residual gain errors with the Giant Metrewave Radio Telescope like array and estimate the bias in the power spectrum. Our results indicate that in order to estimate the redshifted 21-cm power spectrum, better calibration techniques, and estimator development are required.
Discovery of β Cep pulsations in the eclipsing binary V453 Cygni
Authors: Southworth John , Bowman D M , Tkachenko A , Pavlovski K
Published: May 2020

V453 Cyg is an eclipsing binary containing 14 and 11 $\, {\rm M}_\odot$ stars in an eccentric short-period orbit. We have discovered β Cep-type pulsations in this system using Transiting Exoplanet Survey Satellite data. We identify seven significant pulsation frequencies, between 2.37 and 10.51 d−1, in the primary star. These include six frequencies that are separated by yet significantly offset from harmonics of the orbital frequency, indicating they are tidally perturbed modes. We have determined the physical properties of the system to high precision: V453 Cyg A is the first β Cep pulsator with a precise mass measurement. The system is a vital tracer of the physical processes that govern the evolution of massive single and binary stars.
mmCSM-AB: guiding rational antibody engineering through multiple point mutations
Authors: Myung Yoochan , Pires Douglas E V , Ascher David B
Published: May 2020

While antibodies are becoming an increasingly important therapeutic class, especially in personalized medicine, their development and optimization has been largely through experimental exploration. While there have been many efforts to develop computational tools to guide rational antibody engineering, most approaches are of limited accuracy when applied to antibody design, and have largely been limited to analysing a single point mutation at a time. To overcome this gap, we have curated a dataset of 242 experimentally determined changes in binding affinity upon multiple point mutations in antibody-target complexes (89 increasing and 153 decreasing binding affinity). Here, we have shown that by using our graph-based signatures and atomic interaction information, we can accurately analyse the consequence of multi-point mutations on antigen binding affinity. Our approach outperformed other available tools across cross-validation and two independent blind tests, achieving Pearson's correlations of up to 0.95. We have implemented our new approach, mmCSM-AB, as a web-server that can help guide the process of affinity maturation in antibody design. mmCSM-AB is freely available at http://biosig.unimelb.edu.au/mmcsm_ab/.
Metagenomic profiling of gut microbiome in early chronic kidney disease
Authors: Sato Noriaki , Kakuta Masanori , Hasegawa Takanori , Yamaguchi Rui , Uchino Eiichiro , Murashita Koichi , Nakaji Shigeyuki , Imoto Seiya , Yanagita Motoko , Okuno Yasushi
Published: May 2020

Background

The relationship between chronic kidney disease (CKD) and the gut microbiome, which interact through chronic inflammation, uraemic toxin production and immune response regulation, has gained interest in the development of CKD therapies. However, reports using shotgun metagenomic analysis of the gut microbiome are scarce, especially for early CKD. Here we characterized gut microbiome differences between non-CKD participants and ones with early CKD using metagenomic sequencing.

Methods

In total, 74 non-CKD participants and 37 participants with early CKD were included based on propensity score matching, controlling for various factors including dietary intake. Stool samples were collected from participants and subjected to shotgun sequencing. Bacterial and pathway abundances were profiled at the species level with MetaPhlAn2 and HUMAnN2, respectively, and overall microbiome differences were determined using Bray–Curtis dissimilarities. Diabetic and non-diabetic populations were analysed separately.

Results

For diabetic and non-diabetic participants, the mean estimated glomerular filtration rates of the CKD group were 53.71 [standard deviation (SD) 3.87] and 53.72 (SD 4.44), whereas those of the non-CKD group were 72.63 (SD 7.72) and 76.10 (SD 9.84), respectively. Alpha and beta diversities were not significantly different between groups. Based on taxonomic analysis, butyrate-producing species Roseburia inulinivorans, Ruminococcus torques and Ruminococcus lactaris were more abundant in the non-CKD group, whereas Bacteroides caccae and Bacteroides coprocora were more abundant in the non-diabetic CKD group.

Conclusions

Although gut microbiome changes in individuals with early CKD were subtle, the results suggest that changes related to producing short-chain fatty acids can already be observed in early CKD.
Efficacy and safety of oral tolvaptan in patients undergoing hemodialysis: a Phase 2, double-blind, randomized, placebo-controlled trial
Authors: Ogata Hiroaki , Shimofurutani Naoko , Okada Tadashi , Nagamoto Hisashi , Akizawa Tadao
Published: May 2020

Background

Loop diuretics are used to manage fluid retention in patients with end-stage kidney disease undergoing hemodialysis (HD). This randomized, double-blind, placebo-controlled, Phase 2 trial evaluated the efficacy and safety of tolvaptan, a vasopressin V2 receptor antagonist, in Japanese HD patients.

Methods

A total of 124 patients (24-h urine volume ≥500 mL) on thrice-weekly HD were randomized to receive oral tolvaptan 15 mg/day (n = 40), tolvaptan 30 mg/day (n = 40) or placebo (n = 44) for 24 weeks. Efficacy endpoints were change from baseline in 24-h urine volume, total fluid removal by HD per week and interdialytic weight gain (IDWG). Safety was assessed via the incidence of treatment-emergent adverse events (TEAEs).

Results

At treatment end, the difference (95% confidence interval) from the placebo group in the mean change from baseline in 24-h urine volume was significant in the tolvaptan 15 mg {429.1 mL [95% confidence interval (CI) 231.0, 627.2]; P < 0.0001} and 30 mg [371.6 mL (95% CI 144.1, 599.2); P = 0.0017] groups. The mean changes from baseline in total fluid removal by HD and IDWG were not significantly different in the tolvaptan groups versus the placebo group. Although the proportion of patients with TEAEs was lower in the placebo group (77.3%) than in the tolvaptan groups (92.3%), tolvaptan was safe and well-tolerated during the study period.

Conclusions

Tolvaptan significantly sustained diuretic action for 24 weeks in HD patients but did not reduce total fluid removal by HD per week and IDWG to the same extent.
Differentiating Between 2019 Novel Coronavirus Pneumonia and Influenza Using a Nonspecific Laboratory Marker–Based Dynamic Nomogram
Authors: Wang Linghang , Liu Yao , Zhang Ting , Jiang Yuyong , Yang Siyuan , Xu Yanli , Song Rui , Song Meihua , Wang Lin , Zhang Wei , Han Bing , Yang Li , Fan Ying , Cheng Cheng , Wang Jingjing , Xiang Pan , Pu Lin , Xiong Haofeng , Li Chuansheng , Zhang Ming , Tan Jianbo , Chen Zhihai , Liu Jingyuan , Wang Xianbo
Published: May 2020

Background

There is currently a lack of nonspecific laboratory indicators as a quantitative standard to distinguish between the 2019 coronavirus disease (COVID-19) and an influenza A or B virus infection. Thus, the aim of this study was to establish a nomogram to detect COVID-19.

Methods

A nomogram was established using data collected from 457 patients (181 with COVID-19 and 276 with influenza A or B infection) in China. The nomogram used age, lymphocyte percentage, and monocyte count to differentiate COVID-19 from influenza.

Results

Our nomogram predicted probabilities of COVID-19 with an area under the receiver operating characteristic curve of 0.913 (95% confidence interval [CI], 0.883–0.937), greater than that of the lymphocyte:monocyte ratio (0.849; 95% CI, 0.812–0.880; P = .0007), lymphocyte percentage (0.808; 95% CI, 0.768–0.843; P < .0001), monocyte count (0.780; 95% CI, 0.739–0.817; P < .0001), or age (0.656; 95% CI, 0.610–0.699; P < .0001). The predicted probability conformed to the real observation outcomes of COVID-19, according to the calibration curves.

Conclusions

We found that age, lymphocyte percentage, and monocyte count are risk factors for the early-stage prediction of patients infected with the 2019 novel coronavirus. As such, our research provides a useful test for doctors to differentiate COVID-19 from influenza.
Modifying and Evaluating the Opioid Overdose Knowledge Scale for Prescription Opioids: A Pilot Study of the Rx-OOKS
Authors: Shoup Jo Ann , Mueller Shane R , Binswanger Ingrid A , Williams Anna V , Strang John , Glanz Jason M
Published: May 2020

Objective

To develop a validated instrument that measures knowledge about prescription opioid overdose.

Methods

Within an integrated health care system, we adapted, piloted, and tested the reliability and predictive validity of a modified Opioid Overdose Knowledge Scale (OOKS) instrument specific to prescription opioids (Rx-OOKS) with a patient population prescribed long-term opioid therapy and potentially at risk of opioid overdose. We used an interdisciplinary team approach and patient interviews to adapt the instrument. We then piloted the survey on a patient sample and assessed it using Cronbach’s alpha and logistic regression.

Results

Rx-OOKS (N = 56) resulted in a three-construct, 25-item instrument. Internal consistency was acceptable for the following constructs: “signs of an overdose” (10 items) at α = 0.851, “action to take with opioid overdose” (seven items) at α = 0.692, and “naloxone use knowledge” (eight items) at α = 0.729. One construct, “risks of an overdose” (three items), had an α of 0.365 and was subsequently eliminated from analysis due to poor performance. We conducted logistic regression to determine if any of the constructs was strongly associated with future naloxone receipt. Higher scores on “actions to take in an overdose” had nine times the odds of receiving naloxone (odds ratio [OR] = 9.00, 95% confidence interval [CI] = 1.42–57.12); higher “naloxone use knowledge” scores were 15.8 times more likely to receive naloxone than those with lower scores (OR = 15.83, 95% CI = 1.68–149.17).

Conclusions

The Rx-OOKS survey instrument can reliably measure knowledge about prescription opioid overdose recognition and naloxone use. Further, knowledge about actions to take during an opioid overdose and naloxone use were associated with future receipt of naloxone.
Occupational class and educational level inequalities in major cardiovascular risk factors in Turkey: 2008–2016
Authors: Erkoyun Erdem , Mackenbach J P
Published: May 2020

Background

We aimed to investigate the magnitude of occupational class (OC) and educational level (EL) inequalities in cardiovascular risk factors in Turkey from 2008 to 2016 and compare these inequalities with neighbouring European countries.

Methods

We used the Turkey Health Survey among a representative sample of the Turkish population. We estimated relative index of inequality (RII) for four cardiovascular risk factors (obesity/overweight, hypertension, diabetes, smoking) by OC/EL with an interaction term for survey year and compared selected results with neighbouring countries.

Results

Men with lower OC and EL smoked more (e.g. RII for EL = 1.40 [1.26–1.55]); however, the remaining risk factors were mostly lower in these groups. Women in lower socio-economic groups smoked less (e.g. RII for EL = 0.36 [0.29–0.44]), however, had higher prevalence of the remaining risk factors. Significant interactions with survey year were only found in a few cases. The pattern of inequalities in Turkey is largely similar to neighbouring countries.

Conclusions

Inequalities in cardiovascular risk factors are less systematic in Turkey than in most high-income countries, but ongoing trends suggest that this may change in the future.
Does Herding Undermine the Trust Enhancing Effect of Reputation? An Empirical Investigation with Online-Auction Data
Authors: Przepiorka Wojtek , Aksoy Ozan
Published: May 2020

In today’s online markets, the reputation mechanism undergoes its most successful propagation in human history. Online reputation systems substitute informal sanctioning mechanisms at work in close-knit groups and enable complete strangers to trade with each other across large geographic distances. The organizational features of online markets support actors in solving three problems that hamper mutually beneficial market exchange: the value, competition, and cooperation problems. However, due to the plethora of trading opportunities available online, actors face a problem of excess, i.e., the difficulty of choosing a trading partner. Imitation of other actors’ choices of trading partners (i.e., herding) can solve the problem of excess but at the same time lead to the neglect of information about these trading partners’ trustworthiness. Using a large set of online-auction data (N ≈ 88 k), we investigate whether herding as a strategy for solving the problem of excess undermines the reputation mechanism in solving the cooperation problem. Our analysis shows that although buyers follow others in their decisions of which offers to consider, they do not follow others at any price and refer to sellers’ reputations to establish seller trustworthiness. Our results corroborate that reputation systems are viable organizational features that promote mutually beneficial exchanges in anonymous online markets.
Electroencephalographic changes associated with subjective under- and overestimation of sleep duration
Authors: Lecci Sandro , Cataldi Jacinthe , Betta Monica , Bernardi Giulio , Heinzer Raphaël , Siclari Francesca
Published: May 2020

Feeling awake although sleep recordings indicate clear-cut sleep sometimes occurs in good sleepers and to an extreme degree in patients with so-called paradoxical insomnia. It is unknown what underlies sleep misperception, as standard polysomnographic (PSG) parameters are often normal in these cases. Here we asked whether regional changes in brain activity could account for the mismatch between objective and subjective total sleep times (TST). To set cutoffs and define the norm, we first evaluated sleep perception in a population-based sample, consisting of 2,092 individuals who underwent a full PSG at home and estimated TST the next day. We then compared participants with a low mismatch (normoestimators, n = 1,147, ±0.5 SD of mean) with those who severely underestimated (n = 52, <2.5th percentile) or overestimated TST (n = 53, >97.5th percentile). Compared with normoestimators, underestimators displayed higher electroencephalographic (EEG) activation (beta/delta power ratio) in both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, while overestimators showed lower EEG activation (significant in REM sleep). To spatially map these changes, we performed a second experiment, in which 24 healthy subjects and 10 insomnia patients underwent high-density sleep EEG recordings. Similarly to underestimators, patients displayed increased EEG activation during NREM sleep, which we localized to central-posterior brain areas. Our results indicate that a relative shift from low- to high-frequency spectral power in central-posterior brain regions, not readily apparent in conventional PSG parameters, is associated with underestimation of sleep duration. This challenges the concept of sleep misperception, and suggests that instead of misperceiving sleep, insomnia patients may correctly perceive subtle shifts toward wake-like brain activity.
Effects of grinding method and particle size of wheat grain on energy and nutrient digestibility in growing and finishing pigs
Authors: Acosta Jesus A , Petry Amy L , Gould Stacie A , Jones Cassandra K , Stark Charles R , Fahrenholz Adam , Patience John F
Published: May 2020

Feed grains are processed to improve their value in pig diets by exposing kernel contents to enzymatic and microbial action. The objective of this study was to quantify the effect of reducing mean particle size (PS) of wheat grain ground with two different grinding methods (GMs) on the apparent total tract digestibility (ATTD) of nutrients and energy in growing and finishing pigs. Forty-eight barrows were housed in individual pens for 11 d for two periods. Pigs were randomly assigned to a 3 × 2 × 2 factorial experimental design: three target mean PS of wheat grain (300, 500, and 700 µm), two GMs (roller mill and hammermill), and two body weight (BW) periods (growing period; initial BW of 54.9 ± 0.6 kg and finishing period; initial BW of 110.7 ± 1.4 kg). Diets contained one of six hard red wheat grain samples, vitamins, minerals, and titanium dioxide as an indigestible marker. Feed allowance provided 2.5 (for the two lightest pigs in each treatment) or 2.7 (for the remaining six pigs in each treatment) times the estimated daily maintenance energy requirement for each growth stage. Fecal samples were collected for the last 3 d of each period. Data were analyzed as a linear mixed model with pig as a random effect and PS, GM, and BW period and their interactions as fixed effects utilizing the MIXED procedure of SAS. Growing pigs had greater (P < 0.05) ATTD of dry matter (DM), gross energy (GE), N, acid hydrolyzed ether extract (AEE), and neutral detergent fiber (NDF) by lowering mean PS from 700 to 500 μm using either a roller mill or a hammermill. However, digestibility did not increase when PS was reduced from 500 to 300 μm, except for AEE (P < 0.05). Finishing pigs had greater ATTD of DM, GE, N, AEE, and NDF by lowering mean PS with a hammermill from 700 to 500 μm (P < 0.05), but it was greater for 500 μm than for 300 μm (P < 0.05). Using a roller mill reduced the ATTD of DM and NDF by lowering PS from 700 to 300 μm (P < 0.05). The ATTD of GE decreased by lowering PS from 700 to 500 μm with a roller mill (P < 0.05) for finishing pigs. The ATTD of N and AEE for finishing pigs were similar from 700 to 300 μm when ground by a roller mill. These data suggest that the PS that maximized digestibility for a hammermill is 500 μm for both growing and finishing pigs. However, for the roller mill, the PS resulting in the best digestibility were 500 and 700 μm for growing and finishing pigs, respectively.
Genetic Determinants of Reduced Arsenic Metabolism Efficiency in the 10q24.32 Region Are Associated With ReducedAS3MTExpression in Multiple Human Tissue Types
Authors: Chernoff Meytal , Tong Lin , Demanelis Kathryn , Vander Griend Donald , Ahsan Habib , Pierce Brandon L
Published: May 2020

Approximately 140 million people worldwide are exposed to inorganic arsenic through contaminated drinking water. Chronic exposure increases risk for cancers as well as cardiovascular, respiratory, and neurologic diseases. Arsenic metabolism involves the AS3MT (arsenic methyltransferase) gene, and arsenic metabolism efficiency (AME, measured as relative concentrations of arsenic metabolites in urine) varies among individuals. Inherited genetic variation in the 10q24.32 region, containing AS3MT, influences AME, but the mechanisms remain unclear. To better understand these mechanisms, we use tissue-specific expression data from GTEx (Genotype-tissue Expression project) to identify cis-eQTLs (expression quantitative trait loci) for AS3MT and other nearby genes. We combined these data with results from a genome-wide association study of AME using “colocalization analysis,” to determine if 10q24.32 SNPs (single nucleotide polymorphisms) that affect AME also affect expression of AS3MT or nearby genes. These analyses identified cis-eQTLs for AS3MT in 38 tissue types. Colocalization results suggest that the casual variant represented by AME lead SNP rs4919690 impacts expression of AS3MT in 13 tissue types (> 80% probability). Our results suggest this causal SNP also regulates/coregulates expression of nearby genes: BORCS7 (43 tissues), NT5C2 (2 tissues), CYP17A1-AS1 (1 tissue), and RP11-724N1.1 (1 tissue). The rs4919690 allele associated with decreased AME is associated with decreased expression of AS3MT (and other coregulated genes). Our study provides a potential biological mechanism for the association between 10q24.32 variation and AME and suggests that the causal variant, represented by rs4919690, may impact AME (as measured in urine) through its effects on arsenic metabolism occurring in multiple tissue types.
Altered oligodendroglia and astroglia in chronic traumatic encephalopathy
Authors: Chancellor K. Blake , Chancellor Sarah E. , Duke-Cohan Joseph E. , Huber Bertrand R. , Stein Thor D. , Alvarez Victor E. , Okaty Benjamin W. , Dymecki Susan M. , McKee Ann C.
Published: May 2020

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts (RHI)1–6. White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level2,7,8. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls. Analyzing these profiles using unbiased clustering approaches, we identified eighteen transcriptomically distinct cell groups (clusters), reflecting cell types and/or cell states, of which a subset showed differences between CTE and control tissue. Independent in situ methods applied on tissue sections adjacent to that used in the single-nucleus RNA-seq work yielded similar findings. Oligodendrocytes were found to be most severely affected in the CTE white matter samples; they were diminished in number and altered in relative proportions across subtype clusters. Further, the CTE-enriched oligodendrocyte population showed greater abundance of transcripts relevant to iron metabolism and cellular stress response. CTE tissue also demonstrated excessive iron accumulation histologically. Astrocyte alterations were more nuanced; total astrocyte number was indistinguishable between CTE and control samples, but transcripts associated with neuroinflammation were elevated in the CTE astrocyte groups as compared to controls. These results demonstrate specific molecular and cellular differences in CTE oligodendrocytes and astrocytes and may provide a starting point for the development of diagnostics and therapeutic interventions.
Immunomagnetic Sequential Ultrafiltration (iSUF) Platform for Enrichment and Purification of Extracellular Vesicles from Biofluids
Authors: Zhang Jingjing , Nguyen Luong TH , Hickey Richard , Walters Nicole , Wang Xinyu , Kwak Kwang Joo , Lee L. James , Palmer Andre F. , Reátegui Eduardo
Published: May 2020

Extracellular vesicles (EVs) derived from tumor cells have the potential to provide a much-needed source of non-invasive molecular biomarkers for liquid biopsies. However, current methods for EV isolation have limited specificity towards tumor-derived EVs that limit their clinical use. Here, we present an approach called immunomagnetic sequential ultrafiltration (iSUF) that consists of sequential stages of purification and enrichment of EVs (nonspecifically and specifically) in approximately 2 h. In iSUF, EVs present in different volumes of biofluids (0.5 mL to 100 mL) can be significantly enriched (up to 1000 times), with up to 99 % removal of contaminating proteins (e.g., albumin). The EV recovery rate by iSUF for cell culture media (CCM), serum, and urine corresponded to 98.0% ± 3.6%, 96.0% ± 2.0% and 94.0% ± 1.9%, respectively (p > 0.05). The final step of iSUF enables the separation of tumor-specific EVs by incorporating immunomagnetic beads specific to a target subpopulation of EVs. Serum from a small cohort of clinical samples from metastatic breast cancer (BC) patients and healthy donors were processed by the iSUF platform and the isolated EVs from patients showed significantly higher expression levels of BC biomarkers (i.e., HER2, CD24, and miR21).
A mechanistic model of the neural entropy increase elicited by psychedelic drugs
Authors: Herzog Rubén , Mediano Pedro A.M. , Rosas Fernando E. , Carhart-Harris Robin , Perl Yonatan Sanz , Tagliazucchi Enzo , Cofre Rodrigo
Published: May 2020

Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, encoding both acute alterations in consciousness and mediating long-term effects. However, no clear mechanistic explanation for this ‘entropic’ phenomenon has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experimentsin vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain’s anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.