bluuebunny/crossref_metadata_2025 huggingface dataset:
Retracted: Facile synthesis of porous MoS2 nanofibers for efficient drug delivery and cancer treatment
Authors: Liu Shaobo , Wang Yan
Published: June 2021

Porous MoS2 nanofibers were synthesized by electroplating and post-annealing and applied in a responsive drug delivery system. The one-dimensional (1D) MoS2 nanofibers displayed a high specific surface area, controllable morphology, and uniform size, serving as a promising drug carrier for chemotherapy. After surface modification with polyethylene glycol (PEG) through PEGylation, the MoS2/PEG composite displayed excellent physical/chemical stability and biocompatibility. More importantly, MoS2/PEG loaded with doxorubicin (DOX) exhibited a controllable release responsive to pH and near-infrared (NIR) irradiation and demonstrated precise DOX dose release. Such remarkable anticancer effects were mainly attributed to outstanding photothermal performance and stability of porous MoS2 nanofibers. This work offered a new opportunity of employing porous MoS2 nanofibers as drug carriers for effective cancer chemotherapy.
Abelian maps, bi-skew braces, and opposite pairs of Hopf-Galois structures
Authors: Koch Alan
Published: June 2021

Let

G
G

be a finite nonabelian group, and let

ψ
:
G
→
G

\psi :G\to G

be a homomorphism with abelian image. We show how

ψ
\psi

gives rise to two Hopf-Galois structures on a Galois extension

L

/

K

L/K

with Galois group (isomorphic to)

G
G

; one of these structures generalizes the construction given by a “fixed point free abelian endomorphism” introduced by Childs in 2013. We construct the skew left brace corresponding to each of the two Hopf-Galois structures above. We will show that one of the skew left braces is in fact a bi-skew brace, allowing us to obtain four set-theoretic solutions to the Yang-Baxter equation as well as a pair of Hopf-Galois structures on a (potentially) different finite Galois extension.
Macroscopic Quantities of Collective Brain Activity during Wakefulness and Anesthesia
Authors: Ponce-Alvarez Adrián , Uhrig Lynn , Deco Nikolas , Signorelli Camilo M , Kringelbach Morten L , Jarraya Béchir , Deco Gustavo
Published: June 2021

The study of states of arousal is key to understand the principles of consciousness. Yet, how different brain states emerge from the collective activity of brain regions remains unknown. Here, we studied the fMRI brain activity of monkeys during wakefulness and anesthesia-induced loss of consciousness. We showed that the coupling between each brain region and the rest of the cortex provides an efficient statistic to classify the two brain states. Based on this and other statistics, we estimated maximum entropy models to derive collective, macroscopic properties that quantify the system’s capabilities to produce work, to contain information, and to transmit it, which were all maximized in the awake state. The differences in these properties were consistent with a phase transition from critical dynamics in the awake state to supercritical dynamics in the anesthetized state. Moreover, information-theoretic measures identified those parameters that impacted the most the network dynamics. We found that changes in the state of consciousness primarily depended on changes in network couplings of insular, cingulate, and parietal cortices. Our findings suggest that the brain state transition underlying the loss of consciousness is predominantly driven by the uncoupling of specific brain regions from the rest of the network.
Adipokines, Weight Gain and Metabolic and Inflammatory Markers After Antiretroviral Therapy Initiation: AIDS Clinical Trials Group (ACTG) A5260s
Authors: Koethe John R , Moser Carlee , Brown Todd T , Stein James H , Kelesidis Theodoros , Dube Michael , Currier Judith , McComsey Grace A
Published: June 2021

Background

The adipokines leptin and adiponectin, produced primarily by adipose tissue, have diverse endocrine and immunologic effects, and circulating levels reflect adipocyte lipid content, local inflammation, and tissue composition. We assessed relationships between changes in regional fat depots, leptin and adiponectin levels, and metabolic and inflammatory markers over 96 weeks in the AIDS Clinical Trials Group (ACTG) A5260s metabolic substudy of the A5257 randomized trial of tenofovir disoproxil fumarate/emtricitabine plus atazanavir/ritonavir, darunavir/ritonavir, or raltegravir among treatment-naive persons with human immunodeficiency virus (PWH).

Methods

Fat depots were measured using dual-energy absorptiometry and abdominal computed tomographic imaging at treatment initiation and 96 weeks later. Serum leptin and adiponectin, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP) were measured at the same timepoints. Multivariable regression models assessed relationships between fat depots, adipokines, HOMA-IR, and hsCRP at week 96.

Results

Two hundred thirty-four participants maintained viral suppression through 96 weeks (90% male, 29% black, median age 36 years). Serum leptin increased over 96 weeks (mean change 22%) while adiponectin did not (mean change 1%), which did not differ by study arm. Greater trunk, limb, and abdominal subcutaneous and visceral fat were associated with higher HOMA-IR and hsCRP at 96 weeks, but serum leptin level was a stronger determinant of these endpoints using a mediation model approach. A similar mediating effect was not observed for adiponectin.

Conclusions

Higher circulating leptin is associated with greater HOMA-IR and hsCRP independent of fat depot size, suggesting that greater adipocyte lipid content may contribute to impaired glucose tolerance and systemic inflammation among PWH starting antiretroviral therapy.
Impact of Vitamin D and Calcium Supplementation on Bone Mineral Density and Bone Metabolism Among Thai Adolescents With Perinatally Acquired Human Immunodeficiency Virus (HIV) Infection: A Randomized Clinical Trial
Authors: Sudjaritruk Tavitiya , Bunupuradah Torsak , Aurpibul Linda , Kanjanavanit Suparat , Chotecharoentanan Tawalchaya , Sricharoen Natthanidnan , Ounchanum Pradthana , Suntarattiwong Piyarat , Pornpaisalsakul Krittaporn , Puthanakit Thanyawee ,   CAL-D Study Group, Sudjaritruk T , Aurpibul L , Chotecharoentanan T , Sricharoen N , Puthanakit T , Bunupuradah T , Pornpaisalsakul K , Kanjanavanit S , Ounchanum P , Suntarattiwong P
Published: June 2021

Background

To evaluate the impact of vitamin D and calcium supplementation (VitD/Ca) on lumbar spine bone mineral density (LSBMD) and bone metabolism among Thai adolescents with perinatally acquired HIV (PHIVA).

Methods

A multicenter, randomized, active-control, open-labeled trial was conducted. PHIVA (aged 10–20 years) who were on stable cART were enrolled. Baseline LSBMD status was defined as low (z-score ≤ −2) and normal (> −2). Eligible PHIVA were randomly assigned to receive standard-dose (400 IU/1200 mg/day) or high-dose (400 IU/1200 mg/day plus ergocalciferol 20 000 IU/week) VitD/Ca supplementation for 48 weeks (ratio 1:1, stratified by baseline LSBMD). Study outcomes were changes in LSBMD, LSBMD z-scores, and bone metabolism–related biomarkers (25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone [iPTH], C-terminal telopeptide [CTX], procollagen type I amino-terminal propeptide [PINP]) from baseline to week 48.

Results

Among 200 enrolled PHIVA, median age was 16 (IQR:14–18) years; 61% were on NNRTI-based cART. Median 25(OH)D level was 25.5 (IQR: 20.8–33.0) ng/mL. After 48-week VitD/Ca supplementation, LSBMD significantly increased in both treatment groups (high-dose: median: +0.07 [IQR: +0.04 to +0.11] g/cm2; P < .001; standard-dose: +0.09 [+0.03 to +0.13] g/cm2; P < .001). Notably, the change in LSBMD z-scores was significantly greater in high-dose versus standard-dose groups (median: +0.4 [IQR: −0.1 to +0.9] vs +0.1 [−0.4 to +0.7]; P = .02). Levels of 25(OH)D increased, whereas iPTH, CTX, and PINP declined significantly in both groups (P < .05), but no between-group differences were demonstrated.

Conclusions

Over 48-week VitD/Ca supplementation, significant increases in LSBMD, and significant decreases in bone metabolism–related markers were observed among our Thai PHIVA in both treatment groups. The improvement in LSBMD z-score was more enhanced with high-dose VitD/Ca supplementation than standard-dose. High-dose VitD/Ca supplementation might be considered to promote bone health in this population.

Clinical Trials Registration

NCT02426840.
Keynes and Knight on uncertainty: peas in a pod or chalk and cheese?
Authors: Packard Mark D , Bylund Per L , Clark Brent B
Published: June 2021

For many years, the ideas of Knight and Keynes have been widely understood to overlap greatly and they are presumed to have developed notions of uncertainty that deeply intersect, both describing a state where outcomes have non-probabilistic likelihoods. Furthermore, even their political philosophies are historically somewhat homogenised, both considered ‘liberals’. We critically review the historical records and writings of these key scholars with the purpose of dehomogenising their political philosophies, scientific epistemologies and their famous works on uncertainty, published in the same year—1921. We show that neither Keynes nor Knight has been considered fairly by history. Keynes, far from a liberal, was a political socialist who supposed that economic futures could be predicted rationally via deduced probabilities (in an abstract sense) and concluded that expert economists could and should engage in economic planning. Knight, in stark contrast, was something of a radical liberal, holding uncertainty and paradox to be the permeating fact of human existence, which implied, for Knight, significant political and economic complexities far beyond any planner. In short, Knight and Keynes held to radically different philosophic assumptions and, consequently, derived distinctive theories of uncertainty, much further apart than previously supposed. By more fully and accurately placing their ideas within the context of their ideological priors, we gain a stronger sense of how they truly understood the mechanics of economies.
From dishwashing to dishwasher cooking: on social positioning and how users are drawn towards alternative uses of existing technology
Authors: Cardinale Ivano , Runde Jochen
Published: June 2021

Drawing on social positioning theory and using dishwasher cooking as our running example, we examine how users arrive at alternative uses of already-existing technological objects or what we will call ‘user innovations in function’. The first half of the paper provides an abstract account of three forms of structure: social structure, especially as represented by social positions; structures of cognition and action; and the structure of technological objects. The second half theorises user innovations in function as emerging at the nexus of these different forms of structure, with a view to highlighting (i) the pre-reflective and reflective modes of the agency involved; (ii) how these relate to what we call ‘tinkering’ and ‘reflection’ in user innovation; and (iii) the difference between ‘local’ and ‘non-local’ user innovations in function and their possible roots in tinkering or reflection.
Development and Validation of a Novel Indicator of Visual Disability in the National Health and Aging Trends Study
Authors: De Lott Lindsey B , Kolli Ajay , Zhou Yunshu , Hu Mengyao , Ehrlich Joshua R
Published: June 2021

Background and Objectives

The National Health and Aging Trends Study (NHATS) is an ongoing, nationally representative panel study of older adults that collects data on health and disability, including measures on self-reported visual disability (SRVD). Prior studies assessing the association of SRVD with other measures of healthy aging have classified participants as having or not having SRVD, which does not capture the full spectrum of SRVD reported by participants. Therefore, we sought to develop and validate an ordinal indicator of SRVD to facilitate research on the impact of late-life SRVD on health and disability in NHATS.

Research Design and Methods

We used 2015 NHATS data with community-dwelling participants who answered survey questions about visual functioning and vision aid use. Based on responses, participants were categorized into one of 6 groups: blind, near and distance SRVD without vision aid use, near and distance SRVD with vision aid use, near or distance SRVD without vision aid use, near or distance SRVD with vision aid use, or no SRVD. Multivariable Poisson regression models assessed convergent validity of the ordinal SRVD scale with functional activity and well-being scores, while adjusting for demographic factors and medical comorbidities.

Results

Of the 7061 eligible individuals, 8.3% (n = 742) reported SRVD. Using our novel ordinal indicator of SRVD in NHATS, higher levels of SRVD were significantly associated with lower functional activity scores (p < .001 for all) and subjective well-being (p < .001), except for participants reporting blindness. Significant differences between SRVD groups were found, which could not be captured using a binary SRVD variable.

Discussion and Implications

A novel 6-level SRVD scale in NHATS demonstrated convergent validity with functional activity and well-being scales. This scale provides a new tool with improved measurement precision to study the impact of late-life SRVD on health and disability in a nationally representative study of older adults.
Implementation of a school-based physical activity intervention for Brazilian adolescents: a mixed-methods evaluation
Authors: da Silva Bandeira Alexsandra , Pizani Juliana , de Sousa Ana Caroline Ferreira Campos , da Silva Jaqueline Aragoni , Minatto Giseli , Barbosa Filho Valter Cordeiro , Silva Kelly Samara
Published: June 2021

The effectiveness of physical activity interventions can be improved through examining the aspects related to their implementation. However, little such evidence has been collected, particularly in low- and middle-income countries. This study aimed to evaluate the implementation of a school-based physical activity intervention with qualitative and quantitative data from different actors (students, teachers and parents) involved in developing the program. The program was conducted in 2017 with three main components: (i) teacher training, (ii) environmental changes and (iii) educational actions. Mixed-method evaluation was performed by an independent evaluation team using a validated indicator matrix for the implementation process, including the self-reported information of students, teachers and parents, as well as interviews with teachers. In the 3 eligible schools, 350 adolescents (51% girls) answered the implementation questionnaire, as did 45 parents (84% mothers), and 47 teachers (70% female). In the qualitative analysis, 18 teachers participated. Categorical analysis found that the intervention was considered feasible by teachers. In general, teachers had a more positive perception of the implementation than did students. The lack of engagement from the school community and parents and the busy schedule of teachers were indicated to be the main difficulties. In conclusion, despite the teachers’ motivation, some barriers prevented the successful implementation of the program.
Assessing the Impact of Acute Respiratory Illnesses on the Risk of Subsequent Respiratory Illness
Authors: Howard Leigh M , Liu Yuhan , Zhu Yuwei , Liu Dandan , Willams John V , Gil Ana I , Griffin Marie R , Edwards Kathryn M , Lanata Claudio F , Grijalva Carlos G
Published: June 2021

Background

Whether acute respiratory illnesses (ARIs), often associated with virus detection, are associated with lower risk for subsequent ARI remains unclear. We assessed the association between symptomatic ARI and subsequent ARI in young children.

Methods

In a prospective cohort of Peruvian children <3 years, we examined the impact of index ARI on subsequent ARI risk. Index ARI were matched with ≤3 asymptomatic observations and followed over 28 days. We compared risk of subsequent ARI between groups using conditional logistic regression adjusting for several covariates, accounting for repeat observations from individual children.

Results

Among 983 index ARI, 339 (34%) had an ARI event during follow-up, compared with 876/2826 (31%) matched asymptomatic observations. We found no significant association of index ARI and subsequent ARI risk during follow-up overall (adjusted odds ratio [aOR], 1.10; 95% confidence interval [CI], .98–1.23) or when limited to index ARI with respiratory viruses detected (aOR, 1.03; 95% CI, .86–1.24). Similarly, when the outcome was limited to ARI in which viruses were detected, no significant association was seen (aOR, 1.05; 95% CI, .87–1.27).

Conclusions

ARIs were not associated with short-term protection against subsequent ARI in these children. Additional longitudinal studies are needed to understand drivers of recurrent ARI in young children.
Sequential and Concurrent Internet-Telephone Mixed-Mode Designs in Sexual Health Behavior Research
Authors: Legleye Stéphane , Charrance Géraldine
Published: June 2021

The 2013 FECOND (Fertility, Contraception, and Sexual Dysfunction) probability telephone survey aims to monitor sexual health behaviors among fifteen to forty-nine year olds in France. We conducted a random experiment to compare a classic telephone survey (group T, n = 3,846 respondents) with two Internet-telephone mixed-mode protocols: a sequential Internet-telephone protocol (group S, n = 762, among which there were 462 Internet questionnaires), and a concurrent protocol (group C, n = 1,165, among which there were 208 Internet questionnaires). We compare telephone (T), sequential (S), and concurrent (C) samples on cooperation rates, break-off, and item nonresponse rates, sociodemographic characteristics, health behaviors, and seven sexual health behaviors and personal opinions questions. Reports on the most sensitive behaviors were expected to be more truthful and more prevalent on the Internet—and thus in the mixed-mode samples—than in the telephone sample. The cooperation rate (i.e., the response rate among the possible respondents selected during the initial telephone call) was higher in the classic telephone survey than in the sequential and concurrent mixed-mode protocols (88 percent for T versus 77 percent for S and 55 percent for C), where break-off and item nonresponse rates were also higher. Despite these lower response rates, mixed-mode samples showed better representativeness: their marginal distribution of sociodemographic characteristics was closer to that of the 2013 census, and they had higher R-indicators. A causal estimation of the measurement effect resulting from Internet administration found higher prevalence of three out of the seven sexual health behaviors and personal opinions in the sequential protocol compared to the classic telephone group; a similar pattern was found in the concurrent protocol. In addition, the variance of the weights of the mixed-mode protocols is lower, especially for the sequential design. Sequential telephone-Internet mixed-mode protocols nested in a probability telephone survey may be a good way to improve survey research on sensitive behaviors.
The Confiscated Library of William Macintosh in the Bibliothèque Municipale d’Avignon
Authors: Keighren Innes M
Published: June 2021

In 1795, the private library of William Macintosh, author of Travels in Europe, Asia, and Africa (1782), was seized from his home in Avignon by the revolutionary authorities. Using the inventory of this seizure as a guide, this note presents a reconstruction of Macintosh’s library and identifies those books that exist today in the collections of the Bibliothèque municipale d’Avignon.
Redshift-space distortions with split densities
Authors: Paillas Enrique , Cai Yan-Chuan , Padilla Nelson , Sánchez Ariel G
Published: June 2021

Accurate modelling of redshift-space distortions (RSD) is challenging in the non-linear regime for two-point statistics e.g. the two-point correlation function (2PCF). We take a different perspective to split the galaxy density field according to the local density, and cross-correlate those densities with the entire galaxy field. Using mock galaxies, we demonstrate that combining a series of cross-correlation functions (CCFs) offers improvements over the 2PCF as follows: (1) The distribution of peculiar velocities in each split density is nearly Gaussian. This allows the Gaussian streaming model for RSD to perform accurately within the statistical errors of a ($1.5\, h^{-1}$ Gpc)3 volume for almost all scales and all split densities. (2) The probability distribution of the density contrast at small scales is non-Gaussian, but the CCFs of split densities capture the non-Gaussianity, leading to improved cosmological constraints over the 2PCF. We can obtain unbiased constraints on the growth parameter fσ12 at the per cent level, and Alcock–Paczynski (AP) parameters at the sub-per cent level with the minimal scale of $15\, h^{-1}{\rm Mpc}$. This is a ∼30 per cent and ∼6 times improvement over the 2PCF, respectively. The diverse and steep slopes of the CCFs at small scales are likely to be responsible for the improved constraints of AP parameters. (3) Baryon acoustic oscillations (BAO) are contained in all CCFs of split densities. Including BAO scales helps to break the degeneracy between the line-of-sight and transverse AP parameters, allowing independent constraints on them. We discuss and compare models for RSD around spherical densities.
The entry geometry and velocity of planetary debris into the Roche sphere of a white dwarf
Authors: Veras Dimitri , Georgakarakos Nikolaos , Mustill Alexander J , Malamud Uri , Cunningham Tim , Dobbs-Dixon Ian
Published: June 2021

Our knowledge of white dwarf planetary systems predominately arises from the region within a few Solar radii of the white dwarfs, where minor planets breakup, form rings and discs, and accrete on to the star. The entry location, angle, and speed into this Roche sphere has rarely been explored but crucially determines the initial geometry of the debris, accretion rates on to the photosphere, and ultimately the composition of the minor planet. Here, we evolve a total of over 105 asteroids with single-planet N-body simulations across the giant branch and white dwarf stellar evolution phases to quantify the geometry of asteroid injection into the white dwarf Roche sphere as a function of planetary mass and eccentricity. We find that lower planetary masses increase the extent of anisotropic injection and decrease the probability of head-on (normal to the Roche sphere) encounters. Our results suggest that one can use dynamical activity within the Roche sphere to make inferences about the hidden architectures of these planetary systems.
High [O iii]/[C ii] surface brightness ratios trace early starburst galaxies
Authors: Vallini L , Ferrara A , Pallottini A , Carniani S , Gallerani S
Published: June 2021

We study the impact of deviations from the Kennicutt–Schmidt relation (quantified by the ‘burstiness’ parameter κs), gas metallicity (Z), and density (n) on the observed [O iii]88 μm/[C ii]158 μm surface brightness ratios (Σ[O iii]/Σ[C ii]) in nine galaxies at z ≈ 6−9. We first discuss possible biases in the measured Σ[O iii]/Σ[C ii] ratios by comparing the data with zoom-in cosmological simulations and then use a Markov Chain Monte Carlo algorithm to derive the best-fitting values of (κs, Z, n). We find that (i) the strongest dependence of Σ[O iii]/Σ[C ii] is on κs; (ii) high ratios identify starburst galaxies with short gas depletion times ($t_{\rm dep}=6-49\, \rm Myr$); (iii) a secondary dependence on density is found, with Σ[O iii]/Σ[C ii]  anticorrelating with n as a result of the lower [O iii] critical density; and (iv) the ratio weakly depends only on Z. The nine galaxies are significantly enriched (Z = 0.2−0.5 Z⊙) and dense n ≈ 101−3 cm−3. This lends further support to the starburst scenario in which a rapid enrichment of the interstellar medium is expected.
Dating individual quasars with the He ii proximity effect
Authors: Worseck Gábor , Khrykin Ilya S , Hennawi Joseph F , Prochaska J Xavier , Farina Emanuele Paolo
Published: June 2021

Constraints on the time-scales of quasar activity are key to understanding the formation and growth of supermassive black holes (SMBHs), quasar triggering mechanisms, and possible feedback effects on their host galaxies. However, observational estimates of this so-called quasar lifetime are highly uncertain (tQ ∼ 104–109 yr), because most methods are indirect and involve many model-dependent assumptions. Direct evidence of earlier activity is gained from the higher ionization state of the intergalactic medium (IGM) in the quasar environs, observable as enhanced Ly α transmission in the so-called proximity zone. Due to the ∼30 Myr equilibration time-scale of He ii in the z ∼ 3 IGM, the size of the He ii proximity zone depends on the time the quasar had been active before our observation ton ≤ tQ, enabling up to ±0.2 dex precise measurements of individual quasar on-times that are comparable to the e-folding time-scale tS ∼ 44 Myr of SMBH growth. Here we present the first statistical sample of 13 quasars whose accurate and precise systemic redshifts allow for measurements of sufficiently precise He ii quasar proximity zone sizes between ≃2 and ≃15 proper Mpc from science-grade Hubble Space Telescope (HST) spectra. Comparing these sizes to predictions from cosmological hydrodynamical simulations post-processed with 1D radiative transfer, we infer a broad range of quasar on-times from ton ≲ 1 Myr to ton > 30 Myr that does not depend on quasar luminosity, black hole mass, or Eddington ratio. These results point to episodic quasar activity over a long duty cycle, but do not rule out substantial SMBH growth during phases of radiative inefficiency or obscuration.
Mechanical diversity and folding intermediates of parallel-stranded G-quadruplexes with a bulge
Authors: Zhang Yashuo , Cheng Yuanlei , Chen Juannan , Zheng Kewei , You Huijuan
Published: June 2021

A significant number of sequences in the human genome form noncanonical G-quadruplexes (G4s) with bulges or a guanine vacancy. Here, we systematically characterized the mechanical stability of parallel-stranded G4s with a one to seven nucleotides bulge at various positions. Our results show that G4-forming sequences with a bulge form multiple conformations, including fully-folded G4 with high mechanical stability (unfolding forces > 40 pN), partially-folded intermediates (unfolding forces < 40 pN). The folding probability and folded populations strongly depend on the positions and lengths of the bulge. By combining a single-molecule unfolding assay, dimethyl sulfate (DMS) footprinting, and a guanine-peptide conjugate that selectively stabilizes guanine-vacancy-bearing G-quadruplexes (GVBQs), we identified that GVBQs are the major intermediates of G4s with a bulge near the 5′ or 3′ ends. The existence of multiple structures may induce different regulatory functions in many biological processes. This study also demonstrates a new strategy for selectively stabilizing the intermediates of bulged G4s to modulate their functions.
Rational gRNA design based on transcription factor binding data
Authors: Bergenholm David , Dabirian Yasaman , Ferreira Raphael , Siewers Verena , David Florian , Nielsen Jens
Published: June 2021

The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has become a standard tool in many genome engineering endeavors. The endonuclease-deficient version of Cas9 (dCas9) is also a powerful programmable tool for gene regulation. In this study, we made use of Saccharomyces cerevisiae transcription factor (TF) binding data to obtain a better understanding of the interplay between TF binding and binding of dCas9 fused to an activator domain, VPR. More specifically, we targeted dCas9–VPR toward binding sites of Gcr1–Gcr2 and Tye7 present in several promoters of genes encoding enzymes engaged in the central carbon metabolism. From our data, we observed an upregulation of gene expression when dCas9–VPR was targeted next to a TF binding motif, whereas a downregulation or no change was observed when dCas9 was bound on a TF motif. This suggests a steric competition between dCas9 and the specific TF. Integrating TF binding data, therefore, proved to be useful for designing guide RNAs for CRISPR interference or CRISPR activation applications.
Determining the phosphorus release of GraINzyme phytase in diets for nursery pigs
Authors: Becker Larissa L , Wensley Madie R , DeRouchey Joel M , Woodworth Jason C , Tokach Mike D , Goodband Robert D , Gebhardt Jordan T , Raab R Michael , Lessard Philip A
Published: June 2021

The objective of this study was to determine the available P (aP) release curve for a new phytase source, GraINzyme Phytase (Agrivida Inc., Woburn, MA), which is expressed in corn containing an engineered Escherichia coli phytase called Phy02. Plant-expressed phytases are created by inserting phytase-encoding genes into plants resulting in their ability to produce seeds with increased concentrations of phytase. A total of 360 pigs (Line 200 × 400, DNA, Columbus, NE, initially 9.9 ± 0.19 kg) were used in a 21-d growth study. Pigs were weaned at approximately 21 d of age, randomly allotted to pens based on initial body weight (BW) and fed common starter diets. From days 18 to 21 postweaning, all pigs were fed a diet containing 0.11% aP. On day 21 postweaning, considered day 0 of the study, pens were blocked by BW and randomly allotted to one of eight dietary treatments with five pigs per pen and nine pens per treatment. Dietary treatments were formulated to include increasing aP derived from either an inorganic P source (0.11%, 0.19%, or 0.27% from monocalcium P) or increasing phytase (150, 250, 500, 1,000, or 1,500 FTU/kg). Diets were corn-soybean meal-based and contained 1.24% standardized ileal digestible Lys. On day 21 of the trial, one pig per pen (weighing closest to the mean pen BW) was euthanized and the right fibula was collected to determine bone ash using the nondefatted processing method. Overall (days 0 to 21), pigs fed increasing aP from inorganic P or phytase had increased (linear, P < 0.002) average daily gain (ADG), average daily feed intake (ADFI), and gain-to-feed (G:F; quadratic, P < 0.05). Bone ash weight (g) and percentage bone ash increased (linear, P < 0.001), with increasing inorganic P or added phytase. Based on the composition of the diets used in this study, the release equations developed for GraINzyme for ADG, G:F, bone ash weight, and percentage bone ash are as follows: aP = (0.255 × FTU)/(1299.969 + FTU), aP = (0.233 × FTU)/(1236.428 + FTU), aP = (45999.949 × FTU)/(462529200 + FTU), and aP = (0.272 × FTU)/(2576.581 + FTU), respectively.
Clinical characteristics, management, and short term outcome of neonates born to mothers with COVID-19 in a tertiary care hospital in India
Authors: Malik Sushma , Surve Suchitra , Wade Poonam , Kondekar Santosh , Sawant Vishal , Shaikh Murtuja , Kuppusamy Periyasamy , Bharmal Ramesh , Mahale Smita D , Modi Deepak N , Gajbhiye Rahul K
Published: June 2021

Lay summary

The current pandemic of COVID-19 has affected all the countries globally. However, the adverse impact of the pandemic is more seen in the low-income and middle-income countries (LMICs). Although there is evidence on the adverse impact of the SARS-CoV-2 on the health of mothers and neonates, the evidence is mainly from high-income countries. For reducing the mortality and morbidity due to COVID-19 in LMICs, there is a need to generate evidence from the LMICs. The present study is a part of the National Registry of pregnant women with COVID-19 in India (PregCovid registry). Our study demonstrates a higher risk of adverse outcomes such as neonatal sepsis and death in the SARS-CoV-2 infected as compared to the non-infected neonates. The study also showed the risk of SARS-CoV-2 infection in 6.3% of neonates born to mothers with COVID-19.

Introduction

We describe the clinical characteristics, management, and short-term outcomes of SARS-CoV-2 neonates born to mothers with COVID-19 in a tertiary care hospital in Mumbai, India.

Methods

The study is a retrospective analysis of 524 neonates born to mothers with COVID-19 admitted from 14th April 2020 to 31st July 2020.

Results

SARS-CoV-2 infection was detected in 6.3% of the newborns of the mothers with COVID-19. No significant differences were observed between maturity at gestation, birth weight and sex of SARS-CoV-2 infected and non-infected newborns. The risk of sepsis was 4.09 (95% CI,1.28-13.00) fold higher in the neonates with SARS-CoV-2 as compared to the non-infected group (p = 0.031). Poor feeding was significantly more common among SARS-CoV-2 infected neonates (12.1%) as compared to the non-infected neonates (2.7%) (p = 0.017). There was a total of 13 neonatal deaths, of which 3 deaths occurred in SARS-CoV-2 infected neonates (9%) while 10 (3%) in the SAR-CoV-2 negative group. The risk of neonatal death was higher in SARS-CoV-2 infected newborns (OR 4.8; 95% CI 1.25-18.36).

Conclusion

Neonatal SARS-CoV-2 infection is observed in almost 6% of neonates born to mothers with perinatal COVID-19. There is a higher risk of adverse outcomes such as neonatal sepsis and death in the SARS-CoV-2 infected as compared to the non-infected neonates.
Magnetic Resonance Imaging of Ankle Ligaments
Authors: Cledera Thurl Hugh C. , Flores Dyan V.
Published: June 2021

Ankle sprains are a common sports injury that can lead to chronic symptoms and residual instability. Ankle ligaments may be classified into four groups. This article reviews anatomy, MRI features, mechanisms of injury, and associated pathology of ankle ligaments.
A Quality Education
Authors: Murphy Tyler J. , Saldivar Brittany N. , Holland Carolyn K. , Lossius Michele N.
Published: June 2021

Structured quality improvement and patient safety (QI/PS) education has increased at every level of medical education; however, great variability exists in the content taught. Here, the authors present a longitudinal model for medical student QI/PS education that is currently implemented at the University of Florida College of Medicine. The curriculum is taught with a variety of teaching methods incorporated into each year with increasing levels of clinical implementation. This curriculum is multimodal and introduces students to QI/PS concepts, presents mock scenarios, and eventually encourages clinical application to situations students experience during their own clinical practice. Additionally, a specialized track for students to have further immersion into this field of medicine is described, which involves specialized training, expanded educational opportunities, and a capstone project. Both the curriculum and specialized track contain explicit clinical integration to ensure students are prepared to enter the medical profession to engage in QI/PS endeavors.
I-PSI
Authors: Prabhu Vinay , Mikhly Mark , Chung Ryan , Phillips Donna P. , Hochman Katherine A.
Published: June 2021

Despite benefits of safety event reporting, few are trainee initiated. A comprehensive intervention was created to increase trainee reporting, partnering a trainee safety council with high-level faculty. Data were collected for 12 months pre intervention and 30 months post intervention, including short-term (1–12 mo) and long-term (13–30 mo) follow-up. A total of 2337 trainee events were submitted over the study period, primarily communication-related (40%) and on the medicine service (39%). Monthly submissions increased from 29.3 pre intervention to 66.2, 77.7, and 58.6 events/mo at post intervention, short-term follow-up, and long-term follow-up, respectively (P < 0.001). Proportion of hospital events submitted by trainees increased from 2.3% pre intervention to 4.1%, 4.9%, and 3.6% at post intervention, short-term, and long-term follow-up, respectively (P < 0.001). Trainee monthly submissions (P = 0.015) and proportion of hospital events (P < 0.001) declined from short- to long-term follow-up. Low- and intermediate-level harm events significantly increased post intervention (P < 0.001) while high-level events did not (P = 0.15–1.0). Our comprehensive intervention increased trainee event submissions at long-term follow-up.
Time to Reconsider Monoamine Oxidase Inhibitors for Obsessive Compulsive Disorder?
Authors: Grant Jon E. , Baldwin David S. , Chamberlain Samuel R.
Published: June 2021

Purpose/Background

Despite the availability of a range of efficacious evidence-based treatments for obsessive-compulsive disorder (OCD), not all patients experience sufficient benefit or are able to tolerate them in practice. Monoamine oxidase inhibitors (MAOIs) show efficacy in the treatment of depression and certain anxiety disorders (such as social anxiety disorder).

Methods/Procedures

We survey the evidence base from case reports, and clinical trials, regarding use of MAOIs in OCD. We then present new data from a case series collected in routine clinical practice in a specialist clinical service.

Findings/Results

In 9 treatment-resistant patients whose OCD had not improved with at least 2 standard treatment trials, 3 had marked clinical improvement (>35% improvement on YBOCS) on phenelzine, 3 had some improvement (15–34.9%), and 3 showed minimal or no improvement (<15%). In the 3 patients who experienced minimal/no improvement, 2 had discontinued early because of lack of tolerability, and the other patient discontinued after 4 weeks because of perceived lack of symptom benefit.

Implications/Conclusions

We suggest that (1) MAOIs in treatment-resistant OCD require appropriate research scrutiny in large-scale randomized controlled trials; and (2) MAOIs merit consideration as a treatment option in individual cases of OCD, particularly in specialist settings where first-line interventions have proven inadequate to manage severe symptoms.
Hidradenitis Suppurativa: An Exploration of Genetic Perturbations and Immune Dysregulation
Authors: Preda-Naumescu Ana , Ahmed Hana N. , Mayo Tiffany T. , Yusuf Nabiha
Published: June 2021

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin condition that poses a significant diagnostic and therapeutic challenge for clinicians, as the underlying etiology and pathogenesis remains unclear. The host of genetic mutations and immune dysfunction has been identified to be involved in the pathogenesis of HS during recent years. These genetic defects, including monogenetic mutations altering subunits of γ-secretase, a protease that functions through Notch signaling to maintain skin appendages, promote epithelial stability, suppress/terminate innate immune responses (ie, Toll-receptors), further have the propensity to induce aberrant cytokine responses that create to a proinflammatory environment, consequently induce hyperkeratosis and promote expression of pro-inflammatory, locally destructive matrix metalloproteinases. Cytokine-driven inflammation propagates the disease state of HS and contributes to the formation of painful subcutaneous nodules, abscesses, and eventually, fistulas and draining sinus tracts. A closer look at genetic mutations linked to the disease may explain the immune perturbations seen in HS. An understanding of the immune cells and inflammatory markers expressed in affected individuals provides insight into disease pathogenesis and can help identify therapeutic targets.
Genetic Predisposition to Numerous Large Ulcerating Basal Cell Carcinomas and Response to Immune Therapy
Authors: Dasgeb Bahar , Youssefian Leila , Saeidian Amir Hossein , Kang Jun , Shi Wenyin , Shoenberg Elizabeth , Ertel Adam , Fortina Paolo , Vahidnezhad Hassan , Uitto Jouni
Published: June 2021

Objective:

Well-defined germ-line mutations in the PTCH1 gene are associated with syndromic multiple basal cell carcinomas (BCCs). Here, we used whole exome sequencing (WES) to identify the role of patched-1 in patients with multiple, unusually large BCCs.

Methods:

A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled. WES was used to identify the pathogenic gene locus.

Results:

Genetic work-up by WES identified a homozygous PTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin. In addition, heterozygous missense mutations were identified in three cancer-associated genes (EPHB2, RET, and GALNT12) in blood cells as well as in lesional and non-lesional skin. We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement. A rapid and sustained response to nivolumab was noted, suggesting that it is an efficacious drug for long-term therapeutic outcome.

Conclusion:

PTCH1, EPHB2, RET, and GALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple, unusually large BCCs.
Allies in Orthopaedic Trauma Surgery
Authors: Cannada Lisa K. , Dart Bradley , Dehghan Niloofar , Jeray Kyle , Miller Anna N.
Published: June 2021

From the casting couch to the board room, the media, and beyond, the topic of sexual harassment and bullying can no longer be ignored. Sexual harassment and bullying in medicine has the potential to be the next big headline on these topics. The culture in medicine and especially the hierarchy in surgery often permit this behavior. To improve the culture in orthopaedic surgery regarding sexual harassment and bullying, education must occur. With education, comes acknowledgment and recognition. This permits an ability to act on and improve the culture. This paper will start the dialogue of this difficult topic and provide a call to action for sexual harassment and bullying to become “Never events”.
Asexual freshwater snails make poor mate choice decisions
Authors: Stork Sydney , Jalinsky Joseph , Neiman Maurine
Published: June 2021

Once-useful traits that no longer contribute to fitness tend to decay over time. Here, we address whether the expression of mating-related traits that increase the fitness of sexually reproducing individuals but are likely less useful or even costly to asexual counterparts seems to exhibit decay in the latter. Potamopyrgus antipodarum is a New Zealand freshwater snail characterized by repeated transitions from sexual to asexual reproduction. The frequent coexistence of sexual and asexual lineages makes P. antipodarum an excellent model for the study of mating-related trait loss. We used a mating choice assay including sexual and asexual P. antipodarum females and conspecific (presumed better choice) vs. heterospecific (presumed worse choice) males to evaluate the loss of behavioral traits related to sexual reproduction. We found that sexual females engaged in mating behaviors with conspecific mating partners more frequently and for a greater duration than with heterospecific mating partners. By contrast, asexual females mated at similar frequency and duration as sexual females, but did not mate more often or for longer duration with conspecific vs. heterospecific males. These results are consistent with a scenario where selection acting to maintain mate choice in asexual P. antipodarum is weak or ineffective relative to sexual females and, thus, where asexual reproduction contributes to the evolutionary decay of mating-related traits in this system.
The Ebola virus matrix protein clusters phosphatidylserine, a critical step in viral budding
Authors: Husby Monica L. , Amiar Souad , Prugar Laura I. , David Emily A. , Plescia Caroline B. , Huie Kathleen E. , Brannan Jennifer M. , Dye John M. , Pienaar Elsje , Stahelin Robert V.
Published: June 2021

Phosphatidylserine (PS) has been shown to be a critical lipid factor in the assembly and spread of numerous lipid enveloped viruses. Here, we describe the ability of the Ebola virus (EBOV) matrix protein eVP40 to induce clustering of PS and promote viral budding in vitro, as well as the ability of an FDA approved drug, fendiline, to reduce PS clustering subsequently reducing virus budding and entry. To gain mechanistic insight into fendiline inhibition of EBOV replication, multiple in vitro assays were employed including imaging, viral budding and viral entry assays. Fendiline reduced the PS content in mammalian cells and PS in the plasma membrane, reducing the ability of VP40 to form new virus particles. Further, particles that do form from fendiline treated cells have altered particle morphology and decreased infectivity capacity. These complementary studies reveal the mechanism by which filovirus matrix proteins cluster PS to enhance viral assembly, budding, and spread from the host cell while also laying the groundwork for fundamental drug targeting strategies.
Potential therapy for progressive vision loss due to PCDH15-associated Usher Syndrome developed in an orthologous Usher mouse
Authors: Sethna Saumil , Zein Wadih M. , Riaz Sehar , Giese Arnaud P. J. , Schultz Julie M. , Duncan Todd , Hufnagel Robert B. , Brewer Carmen C. , Griffith Andrew J. , Redmond T. Michael , Riazuddin Saima , Friedman Thomas B. , Ahmed Zubair M.
Published: June 2021

Usher syndrome type I (USH1) is characterized by congenital deafness, vestibular areflexia, and progressive retinal degeneration with age. The protein-truncating p.Arg245* founder variant of PCDH15 has an ~2% carrier frequency among Ashkenazi Jews, accounting for nearly 60% of their USH1 cases. Here, longitudinal ocular phenotyping in thirteen USH1F individuals harboring the p.Arg245* variant revealed progressive retinal degeneration, leading to severe loss of vision with macular atrophy by the sixth decade. Half of the affected individuals met either the visual acuity or visual field loss definition for legal blindness by the middle of their fifth decade of life. Mice homozygous for p.Arg250* (Pcdh15R250X; equivalent to human p.Arg245*) also have early visual deficits evaluated using electroretinography. Light-dependent translocation of phototransduction cascade proteins, arrestin and transducin, was found to be impaired in Pcdh15R250X mice. Retinal pigment epithelium-(RPE) specific visual retinoid cycle proteins, RPE65 which converts all-trans retinoids to 11-cis retinoids and CRALBP that transports retinoids, and key retinoid levels were also reduced in Pcdh15R250X mice, suggesting a dual role for protocadherin-15 in photoreceptors and RPE. Administration of exogenous 9-cis retinal, an analog of the naturally occurring 11-cis retinal, improved ERG amplitudes in these mutant mice, suggesting a basis for a clinical trial of exogenous FDA approved retinoids to preserve vision in USH1F patients.

In a preclinical setting studying exogenous retinoids using a novel Usher syndrome mouse model, we describe a potential therapy to treat PCDH15-mediated visual dysfunction.