bluuebunny/crossref_metadata_2025 huggingface dataset:
Hunt for the superheavies
Authors: Johnston Hamish
Published: May 2021

Hamish Johnston reviews Superheavy: Making and Breaking the Periodic Table by Kit Chapman
Rethinking nuclear for a greener planet
Authors: Photopoulos Julianna
Published: May 2021

Troels Schönfeldt, co-founder and chief executive of Danish start-up Seaborg Technologies, talks to Julianna Photopoulos about his career in nuclear and particle physics – and how he unintentionally became an “impact entrepreneur”
Fine structure and black holes
Authors: Perkowitz Sidney
Published: May 2021

Black holes remain a fascinating idea in popular physics while inspiring high-level research.
Polymer-based printed electrolytic capacitor and its circuitry application in a low pass filtering, rectifying and energy storage unit
Authors: Rokaya Chakra , Keskinen Jari , Bromels Cat , Schäffner Philipp , Küzeci Erkan , Lupo Donald
Published: May 2021

We report the fabrication of flexible, printed polymer electrolytic capacitors and their implementation in printed electronics applications such as filtering, rectification and energy harvesting and storage. Capacitors were fabricated by depositing conductive polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate onto porous anodized aluminum foil and yielded specific capacitance of 1 µF cm−2. This is far higher than values reported for printed plate capacitors and opens up the possibility of new applications in printed electronics related to filtering and smoothing at low frequencies. In this work, we have used printed polymer electrolytic capacitors to implement a resistor capacitor first order 1.03 kHz passive low pass filter, a full wave bridge rectifier circuit and a piezo-transducer energy harvester. An integrated full wave bridge rectifier based on these devices shows an efficiency of 80.5% at 1 kHz. When integrated with a vibration-motion based flexible piezoelectric transducer, the devices are able to generate and store about 1 mJ energy, which is a sufficient amount of energy for some low power electronics applications.
Gap analysis of emergency department pharmacy services within a multistate, multihospital integrated health system
Authors: Poe Riley C J , Fouth Garrett W , Revak Ellen N
Published: May 2021

Purpose

The purpose of this project was to identify current emergency medicine pharmacist (EMP) practices at each site and create a plan to integrate, align, and optimize pharmacy services across the health system with established American Society of Health-System Pharmacists (ASHP) best practices for EMPs.

Initially, a review was performed of the literature and guidelines from professional organizations relating to EMPs. A survey was distributed across the health system to assess EMP services at each site, and survey results were used to conduct a gap analysis, comparing current practices to established ASHP best practices. The survey identified unique components of each site, including the patient population served and EMP coverage and responsibilities. To prioritize, design, and execute the gap closure plan, a systemwide EMP workgroup was created. The workgroup formulated a toolkit to provide pharmacy leaders, pharmacy informatics, and EMPs resources to facilitate alignment on the prioritized areas.

Conclusion

This project successfully identified gaps in EMP services and alignment with best practices across the health system. Through prioritization of essential EMP responsibilities, workflow standardization, and EHR optimization, a gap closure plan was formulated to align with ASHP best practices.
Molecular and Histological Evidence Detailing Clinically Observed Skin Improvement Following Cryolipolysis
Authors: Stevens W Grant , Gould Daniel J , Pham Linda D , Jimenez Lozano Joel N
Published: May 2021

Background

In addition to body contouring, there is anecdotal and clinical evidence of reduced laxity caused by skin tightening after cryolipolysis. However, it has not been established how cryolipolysis triggers dermal changes.

Objectives

The aim of this study was to investigate the fundamental mechanisms behind clinically observed dermal changes by molecular and immunohistochemistry (IHC) analytical methods.

Methods

This feasibility study involved 7 subjects who received cryolipolysis treatment. Tissue samples were harvested from 3 days to 5 weeks after treatment. RNA-sequencing examined differential gene expression of major collagens. RNA in situ hybridization (RNA-ISH) investigated the distribution of 1 of the gene markers for collagen type I (COL1A1). IHC for procollagen type I, heat shock protein 47 (HSP47), transforming growth factor β (TGF-β), and tropoelastin was performed and quantified.

Results

Gene expression analysis highlighted a gradual upregulation of collagen mRNA genes. RNA-ISH confirmed upregulation of COL1A1 mRNA and showed a homogeneous distribution through the dermis. IHC showed increases in protein expression. Quantification revealed a 3.62-fold increase of procollagen type I (P < 0.0071), a 2.91-fold increase of TGF-β (P < 0.041), a 1.54-fold increase of HSP47 (P < 0.007), and a 1.57-fold increase of tropoelastin (P < 0.39) compared with untreated areas.

Conclusions

This study revealed significant induction of molecular and protein markers of type I collagen, which supports neocollagenesis and may play an essential role in clinically relevant skin improvement. A dermal remodeling process driven by increased TGF-β and higher expression of HSP47 was observed. Overall, these data provide the first evidence of dermal remodeling and clarify the mechanism by which cryolipolysis may induce skin improvement.

Level of Evidence: 4
Intra-Individual Aging of the Facial Skeleton
Authors: Fourgeot Eugénie , Graillon Nicolas , Savoldelli Charles , Dessi Patrick , Adalian Pascal , Michel Justin , Radulesco Thomas
Published: May 2021

Background

Midface skeletal changes through aging have been conceptualized as a clockwise rotation relative to the cranial base. This finding is mainly supported by cross-sectional population studies based on comparisons between groups of individuals in different age ranges. Few papers have evaluated the intra-individual evolution of the facial skeleton, and those that have included only a limited number of patients.

Objectives

The authors sought to analyze the intra-individual evolution of the facial skeleton.

Methods

We conducted a retrospective study including patients who underwent 2 separate facial computed tomography scans (T1 and T2) with a minimum gap of 7 years. Employing 3-dimensional reconstructions, we measured and compared 7 facial angles (glabellar, orbital, piriform, maxillary, subdental, chin, gonial) and 6 facial distances (lacrimal crest, orbital floor, piriform, zygoma, labiomental, gnathion) on both computed tomography scans.

Results

A total of 56 patients (29 males and 27 females) were included. Mean ages at T1 and T2 were 50 and 59 y, respectively. We found a significant decrease between T1 and T2 in facial angles at the midface (glabella, orbital, piriform, and maxillary angles, all P < 0.0001). We found a significant increase in all facial distances between T1 and T2 for the overall population and for men (all P < 0.05). For women, all distances increased, but only piriform and zygoma distances showed significant changes (P < 0.001 and P < 0.04, respectively). Bone remodeling appeared earlier in women.

Conclusions

Our study confirms the clockwise rotation of the midface during aging. This finding could lead to a better understanding of aesthetic medicine practices.
The Contribution of the Lower Third of the Face to Perceived Age: Do Masks Make You Appear Younger?
Authors: Nicksic Peter J , Karczewski Alison M , Zhao Qianqian , Garcia Nicholas A , Michelotti Brett F , Mahajan Ashish Y , Poore Samuel O
Published: May 2021

Background

There is evidence that changes to the midface and lower third of the face in isolation contribute significantly to one’s perception of the overall facial age. Since the spread of the coronavirus disease 2019 (COVID-19), mask wearing has become commonplace. To date, there have been no studies that explore how covering the lower third of the face impacts the perception of age.

Objectives

The authors hypothesized that covering the lower third of the face with a mask will make a person appear younger.

Methods

One hundred consecutive plastic surgery patients were photographed in a standardized fashion, both masked and unmasked. A questionnaire for factors known to contribute to facial aging was administered. These photographs were randomized to 6 judges who estimated the patients’ age and also quantified facial rhytids with the validated Lemperle wrinkle assessment score of 6. Data were analyzed using PROC MIXED analysis.

Results

Masked patients on average appeared 6.17% younger (mean difference = 3.16 years, P < 0.0001). Wrinkle assessment scores were 9.81% lower in the masked group (mean difference = 0.21, P = 0.0003). All subgroups appeared younger in a mask except for patients aged 18 to 40 years chronological age (P = 0.0617) and patients BMI > 35 (P = 0.5084).

Conclusions

The mask group appeared younger and had lower overall and visible wrinkle assessment scores when compared with the unmasked group. This has implications for our understanding of the contributions of the lower third of the face to overall perceived facial age.
Dobutamine stress echocardiography in low-flow, low-gradient aortic stenosis with concomitant severe functional mitral regurgitation: a case report
Authors: Ishizu Kenichi , Isotani Akihiro , Shirai Shinichi , Ando Kenji
Published: May 2021

Background 

Dobutamine stress echocardiography (DSE) in classical low-flow, low-gradient (LFLG) aortic stenosis (AS) is recommended in recent guidelines to differentiate true-severe AS from pseudo-severe AS. However, DSE for patients with concomitant significant mitral regurgitation (MR) is often inaccurate or inconclusive.

Case summary 

A 73-year-old man with a history of coronary artery bypass grafting was referred to our institution with congestive heart failure. Transthoracic echocardiogram showed severe functional MR and LFLG AS. The results of DSE to determine the severity of AS were inconclusive owing to the absence of flow reserve, usually defined as stroke volume increase of ≥20%. In addition, calcium score by computed tomography scan was also inconclusive. Our heart team decided to reassess the severity of AS after percutaneous edge-to-edge mitral valve repair (PMVR), considering the patient’s high surgical risk. Percutaneous edge-to-edge mitral valve repair was uneventful, resulting in marked reduction of MR from severe to trivial. Dobutamine stress echocardiography after PMVR revealed true-severe AS with the presence of flow reserve. Transcatheter aortic valve implantation (TAVI) was performed, and the patient ambulatorily discharged.

Discussion 

The coexistence of significant AS may lead to overestimation of the severity of MR, and reportedly, concomitant MR improves in the majority of patients after TAVI, especially MR of functional aetiology. However, the coexistence of significant MR often leads to inconclusive DSE results because dobutamine stress may worsen MR and fail to increase the stroke volume. In our case, DSE after PMVR was useful to diagnose the true-severe AS for the patient with LFLG AS and severe functional MR.
Bede, the Papacy, and the Emperors of Constantinople
Authors: Lin Sihong
Published: May 2021

This article argues that the historical writings of the Venerable Bede (d. 735) can also be used by scholars examining the political history of the Eastern Roman Empire in the seventh and eighth centuries. Although Byzantinists have increasingly drawn upon texts written in Syriac, Arabic, and other eastern languages in their scholarship, sources composed in the post-Roman West have yet to be utilised to the same extent. Bede is particularly informative for the reigns of Phocas (602–10), Constans II (641–68), and Justinian II (685–95, 705–11), three emperors who were vilified in later Greek sources. By considering the near-contemporary perspectives preserved in Bede’s Ecclesiastical History and Chronicle alongside the eastern evidence, a more nuanced understanding can be reached for these emperors’ final years. Moreover, Bede’s unique reports strengthen the view that papal history should be integrated into studies of imperial politics. The papacy emerges as a loyal partisan of Phocas in 610 and an institution linked to the growing unrest against Constans in the 660s, while in the eighth century Bede recounted that Pope Constantine gave unheeded advice to Justinian prior to his downfall. In all three cases, Bede yields new insights into the ties that bound together Rome and Constantinople, further demonstrating the utility of Latin sources for reconstructing events in the Mediterranean, even at the end of Late Antiquity.
Social Work Competencies in an Academic Medical Center: The Case of Singapore Health Services
Authors: Ow Yong Lai Meng , Goh Soo Cheng , Chew Judith Fong Hsia
Published: May 2021

In 2014, the Singapore Health Services (SingHealth), an academic medical center, implemented a dual-level competency framework for medical social workers; it comprises 23 behavioral descriptors and six competency clusters at the general level and 30 behavioral descriptors and six competency clusters at the advanced level. This study adopted a qualitative approach to explore the experience among medical social workers with supervisory roles in the implementation of this competency framework. Findings showed that implementation of the competency framework lifted professional standards and image of the profession. The competency framework also helped foster stronger networks, trust, and partnerships among SingHealth organizations. Contextual features that influenced its implementation were as follows: workforce capacity and capability, management support, opportunities, training road maps, and staff’s personal life stage. Operationalizing terms used in the competency framework and specifying the validity period of each competency domain within the framework were found to be crucial to its implementation.
Early-Life Exposure to Antibiotics and Risk for Crohn’s Disease: A Nationwide Danish Birth Cohort Study
Authors: Mark-Christensen Anders , Lange Aksel , Erichsen Rune , Frøslev Trine , Esen Buket Öztürk , Sørensen Henrik Toft , Kappelman Michael D
Published: May 2021

Background

Early-life antibiotic use can alter the intestinal flora and modify the risk of developing Crohn disease (CD), but rigorous epidemiological evidence is limited, with inconsistent results.

Methods

We identified all children born in Denmark from 1995 to 2009 and followed them from birth until death, emigration, a diagnosis of CD, or January 1, 2013. Using Cox regression, we assessed the association between antibiotic exposure in the first year of life and subsequent risk for CD, adjusting for sex, degree of urbanization, birth order, birth year, route of delivery, gestational age, smoking during pregnancy, intake of nonsteroidal anti-inflammatory drugs in the first year of life, and family history of CD.

Results

During a median 9.5 years (9.3 million total person-years), CD was diagnosed in 208 of 979,039 children. Antibiotic use in the first year of life was associated with a higher risk of CD (adjusted hazard ratio, 1.4; 95% confidence interval [CI], 1.1-1.8), with the highest risk with ≥6 courses of antibiotics (adjusted hazard ratio, 4.1; 95% CI, 2.0-8.5). A family history of CD did not modify these risk associations. The cumulative risk of CD at the 11th birthday for children exposed to antibiotics in their first year of life was 0.16‰ (95% CI, 0.11‰–0.22‰) compared to 0.11‰ (95% CI, 0.08‰–0.15‰) for children unexposed to antibiotics in their first year of life.

Conclusions

Antibiotic use in the first year of life is associated with a modestly increased risk for CD, although the absolute risk is very low.
Optimal control problem for fractional stochastic delayed systems with noninstantaneous impulses
Authors: Kumar Surendra , Upadhyay Anjali
Published: May 2021

This article investigates the existence of a solution for a class of fractional delayed stochastic differential equations with noninstantaneous impulses and fractional Brownian motion (fBm). Utilizing the theory of fractional calculus, stochastic integrals for fBm and fixed-point technique, we obtain the solvability result for the considered system. Next, we formulate a fractional stochastic optimal control problem for the infinite delayed impulsive system. Finally, the existence of an optimal state-control pair is established using the Balder Theorem. An example is also constructed that exhibits the efficiency of our results.
Isoperiodic Dynamics in Rank 1 Affine Invariant Orbifolds
Authors: Ygouf Florent
Published: May 2021

Let ${\mathcal {M}}$ be a rank 1 affine invariant orbifold in a stratum of the moduli space of flat surfaces. We show that the leaves of the ${\mathcal {M}}$-isoperiodic foliation are either all closed or all dense. In the 2nd case, we establish ergodicity of the foliation with respect to the affine measure on ${\mathcal {M}}$.
Life history of the Big Sandy crayfish Cambarus callainus Thoma, Loughman & Fetzner, 2014 (Decapoda: Astacoidea: Cambaridae), an imperiled crayfish in the central Appalachian coalfields, USA
Authors: Vopal Christopher G , Loughman Zachary J
Published: May 2021

The Big Sandy crayfish, Cambarus callainusThoma, Loughman & Fetzner, 2014, endemic to the Big Sandy River basin in the central Appalachians, USA, was listed by the United States Fish & Wildlife Service as threatened under the Endangered Species Act in 2016 due to limited and declining range. In March 2018 we began a twelve-month study of the species at the Dry Fork watershed in West Virginia, USA and the Russell Fork watershed in Virginia, USA to document annual life history, reveal if seasonal molting occurs, determine the reproductive season and fecundity, and define its life history strategy. Egg-bearing females were only captured in August; however, a single female was collected with free-living craylings in April, suggesting possible overwintering maternal care or a potential early spring oviposition event. Mating likely occurred between May and June and potentially into the fall and early winter. Five to six size-class cohorts were observed, and we speculate that C. callainus could live up to five years or more. Analysis of morphometric data suggests that females undergo form change, displaying larger chelae and wider abdomens. The smallest Form I male collected had a total carapace length (TCL) of 31.5 mm and the smallest Form I female 32.8 mm. The largest male collected was Form I with a TCL of 55.9 mm. Similar to other species of Cambarus, C. callainus appears to exhibit K-selected life history traits: Fewer and larger eggs, relatively longer maternal care, larger but slow growing, and long lived. The life history information described should prove invaluable to those engaging in conservation efforts for this threatened species.
A Chromosome-Level Assembly of Blunt Snout Bream (Megalobrama amblycephala) Genome Reveals an Expansion of Olfactory Receptor Genes in Freshwater Fish
Authors: Liu Han , Chen Chunhai , Lv Maolin , Liu Ning , Hu Yafei , Zhang Hailin , Enbody Erik D , Gao Zexia , Andersson Leif , Wang Weimin
Published: May 2021

The number of olfactory receptor genes (ORs), which are responsible for detecting diverse odor molecules varies extensively among mammals as a result of frequent gene gains and losses that contribute to olfactory specialization. However, how OR expansions/contractions in fish are influenced by habitat and feeding habit and which OR subfamilies are important in each ecological niche is unknown. Here, we report a major OR expansion in a freshwater herbivorous fish, Megalobrama amblycephala, using a highly contiguous, chromosome-level assembly. We evaluate the possible contribution of OR expansion to habitat and feeding specialization by comparing the OR repertoire in 28 phylogenetically and ecologically diverse teleosts. In total, we analyzed > 4,000 ORs including 3,253 intact, 122 truncated, and 913 pseudogenes. The number of intact ORs is highly variable ranging from 20 to 279. We estimate that the most recent common ancestor of Osteichthyes had 62 intact ORs, which declined in most lineages except the freshwater Otophysa clade that has a substantial expansion in subfamily β and ε ORs. Across teleosts, we found a strong association between duplications of β and ε ORs and freshwater habitat. Nearly, all ORs were expressed in the olfactory epithelium (OE) in three tested fish species. Specifically, all the expanded β and ε ORs were highly expressed in OE of M. amblycephala. Together, we provide molecular and functional evidence for how OR repertoires in fish have undergone gain and loss with respect to ecological factors and highlight the role of β and ε OR in freshwater adaptation.
CRISPRloci: comprehensive and accurate annotation of CRISPR–Cas systems
Authors: Alkhnbashi Omer S , Mitrofanov Alexander , Bonidia Robson , Raden Martin , Tran Van Dinh , Eggenhofer Florian , Shah Shiraz A , Öztürk Ekrem , Padilha Victor A , Sanches Danilo S , de Carvalho André C P L F , Backofen Rolf
Published: May 2021

CRISPR–Cas systems are adaptive immune systems in prokaryotes, providing resistance against invading viruses and plasmids. The identification of CRISPR loci is currently a non-standardized, ambiguous process, requiring the manual combination of multiple tools, where existing tools detect only parts of the CRISPR-systems, and lack quality control, annotation and assessment capabilities of the detected CRISPR loci. Our CRISPRloci server provides the first resource for the prediction and assessment of all possible CRISPR loci. The server integrates a series of advanced Machine Learning tools within a seamless web interface featuring: (i) prediction of all CRISPR arrays in the correct orientation; (ii) definition of CRISPR leaders for each locus; and (iii) annotation of cas genes and their unambiguous classification. As a result, CRISPRloci is able to accurately determine the CRISPR array and associated information, such as: the Cas subtypes; cassette boundaries; accuracy of the repeat structure, orientation and leader sequence; virus-host interactions; self-targeting; as well as the annotation of cas genes, all of which have been missing from existing tools. This annotation is presented in an interactive interface, making it easy for scientists to gain an overview of the CRISPR system in their organism of interest. Predictions are also rendered in GFF format, enabling in-depth genome browser inspection. In summary, CRISPRloci constitutes a full suite for CRISPR–Cas system characterization that offers annotation quality previously available only after manual inspection.
A cleavage-based surrogate reporter for the evaluation of CRISPR–Cas9 cleavage efficiency
Authors: Jung Soo Bin , Lee Chae young , Lee Kwang-Ho , Heo Kyu , Choi Si Ho
Published: May 2021

CRISPR–Cas9 is a powerful tool for genome engineering, but its efficiency largely depends on guide RNA (gRNA). There are multiple methods available to evaluate the efficiency of gRNAs, including the T7E1 assay, surveyor nuclease assay, deep sequencing, and surrogate reporter systems. In the present study, we developed a cleavage-based surrogate that we have named the LacI-reporter to evaluate gRNA cleavage efficiency. The LacI repressor, under the control of the EF-1α promoter, represses luciferase or EGFP reporter expression by binding to the lac operator. Upon CRISPR–Cas9 cleavage at a target site located between the EF-1α promoter and the lacI gene, repressor expression is disrupted, thereby triggering luciferase or EGFP expression. Using this system, we can quantitate gRNA cleavage efficiency by assessing luciferase activity or EGFP expression. We found a strong positive correlation between the cleavage efficiency of gRNAs measured using this reporter and mutation frequency, measured using surveyor and deep sequencing. The genome-editing efficiency of gRNAs was validated in human liver organoids. Our LacI-reporter system provides a useful tool to select efficient gRNAs for genome editing.
Homologous recombination, cancer and the ‘RAD51 paradox’
Authors: Matos-Rodrigues Gabriel , Guirouilh-Barbat Josée , Martini Emmanuelle , Lopez Bernard S
Published: May 2021

Genetic instability is a hallmark of cancer cells. Homologous recombination (HR) plays key roles in genome stability and variability due to its roles in DNA double-strand break and interstrand crosslink repair, and in the protection and resumption of arrested replication forks. HR deficiency leads to genetic instability, and, as expected, many HR genes are downregulated in cancer cells. The link between HR deficiency and cancer predisposition is exemplified by familial breast and ovarian cancers and by some subgroups of Fanconi anaemia syndromes. Surprisingly, although RAD51 plays a pivotal role in HR, i.e., homology search and in strand exchange with a homologous DNA partner, almost no inactivating mutations of RAD51 have been associated with cancer predisposition; on the contrary, overexpression of RAD51 is associated with a poor prognosis in different types of tumours. Taken together, these data highlight the fact that RAD51 differs from its HR partners with regard to cancer susceptibility and expose what we call the ‘RAD51 paradox’. Here, we catalogue the dysregulations of HR genes in human pathologies, including cancer and Fanconi anaemia or congenital mirror movement syndromes, and we discuss the RAD51 paradox.
Impact of Bamlanivimab Monoclonal Antibody Treatment on Hospitalization and Mortality Among Nonhospitalized Adults With Severe Acute Respiratory Syndrome Coronavirus 2 Infection
Authors: Bariola J Ryan , McCreary Erin K , Wadas Richard J , Kip Kevin E , Marroquin Oscar C , Minnier Tami , Koscumb Stephen , Collins Kevin , Schmidhofer Mark , Shovel Judith A , Wisniewski Mary Kay , Sullivan Colleen , Yealy Donald M , Nace David A , Huang David T , Haidar Ghady , Khadem Tina , Linstrum Kelsey , Seymour Christopher W , Montgomery Stephanie K , Angus Derek C , Snyder Graham M
Published: May 2021

Background

Monoclonal antibody treatment may prevent complications of coronavirus disease 2019 (COVID-19). We sought to quantify the impact of bamlanivimab monoclonal antibody monotherapy on hospitalization and mortality among outpatients at high risk of COVID-19 complications.

Methods

In this observational study we compared outpatients who received bamlanivimab monoclonal antibody from December 9, 2020 to March 3, 2021 to nontreated patients with a positive polymerase chain reaction or antigen test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the same period who were eligible for monoclonal antibody treatment. The primary outcome was 28-day hospitalization or all-cause mortality, and the secondary outcome was hospitalization or emergency department visit without hospitalization. The risk-adjusted odds of study outcomes comparing bamlanivimab treated and untreated patients was determined using 1:5 propensity matching and multivariable logistic regression.

Results

Among 232 patients receiving bamlanivimab matched with 1160 comparator patients, the mean age was 67 years, 56% were female, and 196 (14%) of patients experienced hospitalization or mortality. After adjustment for propensity to receive treatment, bamlanivimab treatment was associated with a significantly reduced risk-adjusted odds of hospitalization or mortality within 28 days (odds ratio [OR], 0.40; 95% confidence interval [95% CI], 0.24–0.69; P < .001). Bamlanivimab treatment was also associated with a significantly lower risk adjusted odds of hospitalization or emergency department visit without hospitalization (OR, 0.54; 95% CI, 0.35–0.82; P = .004). The results were most strongly associated with patients age 65 years and older.

Conclusions

Bamlanivimab monoclonal antibody monotherapy was associated with reduced hospitalizations and mortality within 28 days among outpatients with mild to moderate COVID-19.

Use of bamlanivimab monotherapy for outpatients with mild to moderate COVID-19 infection was associated with reductions in hospitalizations and mortality within 28 days. Benefit was strongest in those age 65 years or older
From Rab to Raab: The Construction of the Office of First Secretary of State
Authors: Thornton Stephen , Kirkup Jonathan
Published: May 2021

Through information gained from interviews with key political actors, archival research and close examination of biographical material, this article aims to provide the first detailed account of what it means to be the British First Secretary of State. Sometimes regarded simply as a synonym for Deputy Prime Minister, it will be demonstrated that the reality is far more complicated. Not all First Secretaries have been regarded as the Prime Minister’s second-in-command, indeed there have been many years where the post has ceased to exist. Yet, at other times, First Secretaries have led the country, albeit briefly. The main argument to be made is that the office of First Secretary of State is only as important as the person holding that office is perceived to be important, but there is potential for that to change.
Spaceflight decelerates the epigenetic clock orchestrated with a global alteration in DNA methylome and transcriptome in the mouse retina
Authors: Chen Zhong , Stanbouly Seta , Nishiyama Nina C , Chen Xin , Delp Michael D , Qiu Hongyu , Mao Xiao W , Wang Charles
Published: May 2021

Astronauts exhibit an assortment of clinical abnormalities in their eyes during long-duration spaceflight. The purpose of this study was to determine whether spaceflight induces epigenomic and transcriptomic reprogramming in the retina or alters the epigenetic clock. The mice were flown for 37 days in animal enclosure modules on the International Space Station; ground-based control animals were maintained under similar housing conditions. Mouse retinas were isolated and both DNA methylome and transcriptome were determined by deep sequencing. We found that a large number of genes were differentially methylated with spaceflight, whereas there were fewer differentially expressed genes at the transcriptome level. Several biological pathways involved in retinal diseases such as macular degeneration were significantly altered. Our results indicated that spaceflight decelerated the retinal epigenetic clock. This study demonstrates that spaceflight impacts the retina at the epigenomic and transcriptomic levels, and such changes could be involved in the etiology of eye-related disorders among astronauts.
Nitric oxide coordinates growth, development, and stress response via histone modification and gene expression
Authors: Ageeva-Kieferle Alexandra , Georgii Elisabeth , Winkler Barbro , Ghirardo Andrea , Albert Andreas , Hüther Patrick , Mengel Alexander , Becker Claude , Schnitzler Jörg-Peter , Durner Jörg , Lindermayr Christian
Published: May 2021

Nitric oxide (NO) is a signaling molecule with multiple regulatory functions in plant physiology and stress response. In addition to direct effects on transcriptional machinery, NO executes its signaling function via epigenetic mechanisms. We report that light intensity-dependent changes in NO correspond to changes in global histone acetylation (H3, H3K9, and H3K9/K14) in Arabidopsis (Arabidopsis thaliana) wild-type leaves, and that this relationship depends on S-nitrosoglutathione reductase and histone deacetylase 6 (HDA6). The activity of HDA6 was sensitive to NO, demonstrating that NO participates in regulation of histone acetylation. Chromatin immunoprecipitation sequencing and RNA-seq analyses revealed that NO participates in the metabolic switch from growth and development to stress response. This coordinating function of NO might be particularly important in plant ability to adapt to a changing environment, and is therefore a promising foundation for mitigating the negative effects of climate change on plant productivity.
Researcher experiences in practice-based interdisciplinary research
Authors: Leigh Jennifer , Brown Nicole
Published: May 2021

This article reports on a study that followed up on an initial interdisciplinary project and focused specifically on the experiences of researchers involved in practice-based interdisciplinary research. We share an approach to research evaluation that focuses on the experiences of those conducting the research rather than the outputs. The study allowed those involved in the initial successful project to reflect post hoc on their experiences. We show that neglecting fundamental conceptions about how the research is conceptualized can lead to challenges with the research itself. In addition to alternative understandings of research and concepts, practical and logistical issues, whilst seeming trivial, feed into communication issues such as misunderstanding of terms and language. We argue that tensions and confusions around the very nature of the research—what was being researched, and what was valued as research, epistemological differences between the disciplinary perspectives—need to be explored and interrogated in order to maximize the benefits of interdisciplinary research. We conclude with considerations of the relationship between interdisciplinary research in a team and identity work of team members, and the implications this may have for research design, an area of research evaluation that certainly needs further exploration.
A systematic review and network meta-analysis of the safety of early interventional treatments in rheumatoid arthritis
Authors: Adas Maryam A , Allen Victoria B , Yates Mark , Bechman Katie , Clarke Benjamin D , Russell Mark D , Rutherford Andrew I , Cope Andrew P , Norton Sam , Galloway James B
Published: May 2021

Objectives

To evaluate the safety of treatment strategies in patients with early RA.

Methods

Systematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included. Long-term extension studies, post-hoc and pooled analyses and RCTs with no comparator arm were excluded. Serious adverse events, serious infections and non-serious adverse events were extracted from all RCTs, and event rates in intervention and comparator arms were compared using meta-analysis and network meta-analysis (NMA).

Results

From an initial search of 3423 studies, 20 were included, involving 9202 patients. From the meta-analysis, the pooled incidence rates per 1000 patient-years for serious adverse events were 69.8 (95% CI: 64.9, 74.8), serious infections 18.9 (95% CI: 16.2, 21.6) and non-serious adverse events 1048.2 (95% CI: 1027.5, 1068.9). NMA showed that serious adverse event rates were higher with biologic monotherapy than with MTX monotherapy, rate ratio 1.39 (95% CI: 1.12, 1.73). Biologic monotherapy rates were higher than those for MTX and steroid therapy, rate ratio 3.22 (95% CI: 1.47, 7.07). Biologic monotherapy had a higher adverse event rate than biologic combination therapy, rate ratio 1.26 (95% CI: 1.02, 1.54). NMA showed no significant difference between strategies with respect to serious infections and non-serious adverse events rates.

Conclusion

The study revealed the different risk profiles for various early RA treatment strategies. Observed differences were overall small, and in contrast to the findings of established RA studies, steroid-based regimens did not emerge as more harmful.
A Diagnosis and Biotype Comparison Across the Psychosis Spectrum: Investigating Volume and Shape Amygdala-Hippocampal Differences from the B-SNIP Study
Authors: Guimond Synthia , Gu Feng , Shannon Holly , Kelly Sinead , Mike Luke , Devenyi Gabriel A , Chakravarty M Mallar , Sweeney John A , Pearlson Godfrey , Clementz Brett A , Tamminga Carol , Keshavan Matcheri
Published: May 2021

Objective

Brain-based Biotypes for psychotic disorders have been developed as part of the B-SNIP consortium to create neurobiologically distinct subgroups within idiopathic psychosis, independent from traditional phenomenological diagnostic methods. In the current study, we aimed to validate the Biotype model by assessing differences in volume and shape of the amygdala and hippocampus contrasting traditional clinical diagnoses with Biotype classification.

Methods

A total of 811 participants from 6 sites were included: probands with schizophrenia (n = 199), schizoaffective disorder (n = 122), psychotic bipolar disorder with psychosis (n = 160), and healthy controls (n = 330). Biotype classification, previously developed using cognitive and electrophysiological data and K-means clustering, was used to categorize psychosis probands into 3 Biotypes, with Biotype-1 (B-1) showing reduced neural salience and severe cognitive impairment. MAGeT-Brain segmentation was used to determine amygdala and hippocampal volumetric data and shape deformations.

Results

When using Biotype classification, B-1 showed the strongest reductions in amygdala-hippocampal volume and the most widespread shape abnormalities. Using clinical diagnosis, probands with schizophrenia and schizoaffective disorder showed the most significant reductions of amygdala and hippocampal volumes and the most abnormal hippocampal shape compared with healthy controls. Biotype classification provided the strongest neuroanatomical differences compared with conventional DSM diagnoses, with the best discrimination seen using bilateral amygdala and right hippocampal volumes in B-1.

Conclusion

These findings characterize amygdala and hippocampal volumetric and shape abnormalities across the psychosis spectrum. Grouping individuals by Biotype showed greater between-group discrimination, suggesting a promising approach and a favorable target for characterizing biological heterogeneity across the psychosis spectrum.
A Machine Learning Classifier Improves Mortality Prediction Compared With Pediatric Logistic Organ Dysfunction-2 Score: Model Development and Validation
Authors: Prince Remi D. , Akhondi-Asl Alireza , Mehta Nilesh M. , Geva Alon
Published: May 2021

Objectives:

To determine whether machine learning algorithms can better predict PICU mortality than the Pediatric Logistic Organ Dysfunction-2 score.

Design:

Retrospective study.

Setting:

Quaternary care medical-surgical PICU.

Patients:

All patients admitted to the PICU from 2013 to 2019.

Interventions:

None.

Measurements and Main Results:

We investigated the performance of various machine learning algorithms using the same variables used to calculate the Pediatric Logistic Organ Dysfunction-2 score to predict PICU mortality. We used 10,194 patient records from 2013 to 2017 for training and 4,043 patient records from 2018 to 2019 as a holdout validation cohort. Mortality rate was 3.0% in the training cohort and 3.4% in the validation cohort. The best performing algorithm was a random forest model (area under the receiver operating characteristic curve, 0.867 [95% CI, 0.863–0.895]; area under the precision-recall curve, 0.327 [95% CI, 0.246–0.414]; F1, 0.396 [95% CI, 0.321–0.468]) and significantly outperformed the Pediatric Logistic Organ Dysfunction-2 score (area under the receiver operating characteristic curve, 0.761 [95% CI, 0.713–0.810]; area under the precision-recall curve (0.239 [95% CI, 0.165–0.316]; F1, 0.284 [95% CI, 0.209–0.360]), although this difference was reduced after retraining the Pediatric Logistic Organ Dysfunction-2 logistic regression model at the study institution. The random forest model also showed better calibration than the Pediatric Logistic Organ Dysfunction-2 score, and calibration of the random forest model remained superior to the retrained Pediatric Logistic Organ Dysfunction-2 model.

Conclusions:

A machine learning model achieved better performance than a logistic regression-based score for predicting ICU mortality. Better estimation of mortality risk can improve our ability to adjust for severity of illness in future studies, although external validation is required before this method can be widely deployed.
Development and Content Validation of a Multidisciplinary Standardized Management Pathway for Hypoxemic Respiratory Failure and Acute Respiratory Distress Syndrome
Authors: Parhar Ken Kuljit S. , Zjadewicz Karolina , Knight Gwen E. , Soo Andrea , Boyd Jamie M. , Zuege Danny J. , Niven Daniel J. , Doig Christopher J. , Stelfox Henry T.
Published: May 2021

Objectives:

Treatment of hypoxemic respiratory failure and acute respiratory distress syndrome is complex. Evidence-based therapies that can improve survival and guidelines advocating their use exist; however, implementation is inconsistent. Our objective was to develop and validate an evidence-based, stakeholder-informed standardized management pathway for hypoxemic respiratory failure and acute respiratory distress syndrome to improve adherence to best practice.

Design:

A standardized management pathway was developed using a modified Delphi consensus process with a multidisciplinary group of ICU clinicians. The proposed pathway was externally validated with a survey involving multidisciplinary stakeholders and clinicians.

Setting:

In-person meeting and web-based surveys of ICU clinicians from 17 adult ICUs in the province of Alberta, Canada.

Intervention:

Not applicable.

Measurements and Main Results:

The consensus panel was comprised of 30 ICU clinicians (4 nurses, 10 respiratory therapists, 15 intensivists, 1 nurse practitioner; median years of practice 17 [interquartile range, 13–21]). Ninety-one components were serially rated and revised over two rounds of online and one in-person review. The final pathway included 46 elements. For the validation survey, 692 responses (including 59% nurses, 33% respiratory therapists, 7% intensivists and 1% nurse practitioners) were received. Agreement of greater than 75% was achieved on 43 of 46 pathway elements.

Conclusions:

A 46-element evidence-informed hypoxemic respiratory failure and acute respiratory distress syndrome standardized management pathway was developed and demonstrated to have content validity.
SARS-CoV-2 Impairs Vision
Authors: Finsterer Josef , Scorza Fulvio A. , Scorza Carla A. , Fiorini Ana C.
Published: May 2021

Objectives:

Affection of the central nervous system and the eyes is increasingly recognized as manifestations of a SARS-CoV-2 infection (COVID-19). This review aims at summarizing and discussing recent advances concerning causes and locations of impaired vision because of an infection with SARS-CoV-2.

Methods:

On a literature search through PubMed and ScholarOne, all available publications about COVID-19 patients with impaired vision were retrieved.

Results:

Visual impairment in SARS-CoV-2–infected patients may be due to infection of lacrimal glands (dacryoadenitis), conjunctivitis, tonic pupils, vitritis, central retinal artery/venous occlusion, retinitis, retinal bleeding, panuveitis, anterior ischemic optic neuropathy, optic nerve stroke, optic neuritis, optic perineuritis, or occipital ischemic stroke. Visual impairment may be the initial manifestation of SARS-CoV-2.

Conclusions:

This mini review shows that impaired vision may be the initial manifestation of COVID-19, that all sections of the visual tract may be affected and causative for visual impairment in COVID-19 patients, and that SARS-CoV-2 manifests along the visual tract with ischemia, focal infection, and immunological reactions.
New Focus on Endovascular Therapy for Ischemic Stroke
Authors: Kelly Sean , Raz Eytan , Shapiro Maksim , Ishida Koto
Published: May 2021

Background:

Over the past 2 decades, a growing number of large-scale clinical trials have helped expand the toolkit for emergency management of acute ischemic stroke. This article is intended to be an up-to-date resource to aid nonstroke specialist neurology providers and ophthalmologists in identifying situations and patient populations in which urgent stroke evaluation should be completed with options for emergent reperfusion therapy considered.

Evidence Acquisition:

The literature forming the foundation of the guidelines for early management of patients with acute ischemic stroke was reviewed, annotated, and summarized.

Results:

Data from both initial and follow-up trials investigating the benefits and indications for use of intravenous thrombolysis and endovascular intervention for stroke are reviewed systematically, with an emphasis on new updates to qualifying patient populations and time periods for treatment.

Conclusions:

Recent studies underscore the conclusion that timely reperfusion in acute ischemic stroke is the most effective available treatment and that there are a growing number of new scenarios and patients for which interventions maybe applied.
Transplantation of adipose-derived stromal cells protects functional and morphological auditory nerve integrity in a model of cochlear implantation
Authors: Radeloff Andreas , Nada Nashwa , El Mahallawi Trandil , Kolkaila Enaas , Vollmer Maike , Rak Kristen , Hagen Rudolf , Schendzielorz Philipp
Published: May 2021

Cochlear implants are considered the gold standard therapy for subjects with severe hearing loss and deafness. Cochlear implants bypass the damaged hair cells and directly stimulate spiral ganglion neurons (SGNs) of the auditory nerve. Hence, the presence of functional SGNs is crucial for speech perception in electric hearing with a cochlear implant. In deaf individuals, SGNs progressively degenerate due to the lack of neurotrophic support, normally provided by sensory cells of the inner ear. Adipose-derived stromal cells (ASCs) are known to produce neurotrophic factors. In a guinea pig model of sensory hearing loss and cochlear implantation, ASCs were autologously transplanted into the scala tympani prior to insertion of a cochlear implant on one side. Electrically evoked auditory brain stem responses (eABR) were recorded 8 weeks after cochlear implantation. At conclusion of the experiment, the cochleae were histologically evaluated. Compared to untreated control animals, transplantation of ASCs resulted in an increased number of SGNs and their peripheral neurites. In ASC-transplanted animals, mean eABR thresholds were lower and suprathreshold amplitudes larger, suggesting a larger population of intact auditory nerve fibers. Moreover, when compared to controls, amplitude-level functions of eABRs in ASC transplanted animals demonstrated steeper slopes in response to increasing interphase gaps (IPGs), indicative of better functionality of the auditory nerve. In summary, results suggest that transplantation of autologous ASCs into the deaf inner ear may have protective effects on the survival of SGNs and their peripheral processes and may thus contribute to long-term benefits in speech discrimination performance in cochlear implant subjects.