bluuebunny/crossref_metadata_2025 huggingface dataset:
The Sensory Gating Inventory-Brief
Authors: Bailey Allen J , Moussa-Tooks Alexandra B , Klein Samuel D , Sponheim Scott R , Hetrick William P
Published: May 2021

The Sensory Gating Inventory (SGI) is a 36-item measure used to assess an individual’s subjective ability to modulate, filter, over-include, discriminate, attend to, and tolerate sensory stimuli. Due to its theoretical and empirical link with sensory processing deficits, this measure has been used extensively in studies of psychosis and other psychopathology. The current work fills a need within the field for a briefer measure of sensory gating aberrations that maintains the original measure’s utility. For this purpose, large samples (total n = 1552) were recruited from 2 independent sites for item reduction/selection and brief measure validation, respectively. These samples reflected subgroups of individuals with a psychosis-spectrum disorder, at high risk for a psychosis-spectrum disorder, nonpsychiatric controls, and nonpsychosis psychiatric controls. Factor analyses and item-response models were used to create the SGI-Brief (SGI-B; 10 Likert-rated items), a unidimensional self-report measure that retains the original SGI’s transdiagnostic (ie, present across disorders) utility and content breadth. Findings show that the SGI-B has excellent psychometric properties (alpha = 0.92) and demonstrates external validity through strong associations with measures of psychotic symptomatology, theoretically linked measures of personality (eg, perceptual dysregulation), and modest associations with laboratory-based sensory processing tasks in the auditory and visual domains on par with the original version. Accordingly, the SGI-B will be a valuable tool for dimensional and transdiagnostic examination of sensory gating abnormalities within clinical science research, while reducing administrator and participant burden.
Can a charity charge for Filet Mignon?
Authors: Nitikman Joel
Published: May 2021

This article considers whether there is any rule in Canadian charities law or the Canadian Income Tax Act prohibiting a registered charity from charging a fair market fee for the charitable goods or services it provides or from realizing a net surplus of revenues over expenses by charging such a fee. In particular, It considers whether a modern educational institution (such as a private university) may charge a market rate of tuition and remain a charity, even if it realizes a surplus of revenue over expenses while doing so.
Effects of Megasphaera elsdenii administration on performance and carcass traits of finishing Bos indicus feedlot cattle
Authors: Lopes Ana Laura , Santos Flávio A P , Meschiatti Murillo , de Oliveira Mario Olímpio , Fernandes Juliano J R , Drouillard James S , Cappellozza Bruno I
Published: May 2021

This study evaluated the effects of Megasphaera elsdenii administration at the beginning of the feedlot period on performance of Bos taurus indicus bulls. On d 0, 383 Nellore bulls (initial shrunk body weight 384 ± 29.2 kg; initial age = 24 ± 2 mo) were assigned to treatments in a randomized complete block design. Treatments consisted of 1) 14 d adaptation diet and transition to a finishing diet (CONT), 2) CONT plus oral administration of 20 mL of Lactipro-NXT (M. elsdenii) on d 0 of the study (MEG-14), 3) CONT diet, consisting of 6 d of adaptation diet plus oral administration of 20 mL of Lactipro-NXT on d 0 of the study (MEG-6), and 4) No adaptation diet and oral administration of 20 mL of Lactipro-NXT on d 0 of the study (MEG-0). Experimental period lasted 119 d. No treatment effects were observed for any of the performance parameters evaluated herein (P ≥ 0.15). Nonetheless, a treatment × wk interaction was observed for DM, NEm, and NEg intakes (P < 0.0001). For all these parameters, MEG-0 and MEG-6 had a reduced intake vs. MEG-14 and CONT in the first wk of the study (P ≤ 0.05). For the carcass traits, no effects were observed for HCW (P ≥ 0.24), whereas MEG-6 had a greater REA when compared with MEG-0 and MEG-14 (quadratic effect; P = 0.04) and MEG-administered bulls tended to have a greater BFT vs. CONT (P = 0.08). In summary, M. elsdenii administration at the beginning of the feedlot period did not improve performance, whereas reducing the length of the adaptation period for 6 d improved REA of finishing Bos taurus indicus bulls.
Cerebellar and Cortical Correlates of Internal and External Speech Error Monitoring
Authors: Runnqvist Elin , Chanoine Valérie , Strijkers Kristof , Pattamadilok Chotiga , Bonnard Mireille , Nazarian Bruno , Sein Julien , Anton Jean-Luc , Dorokhova Lydia , Belin Pascal , Alario F- Xavier
Published: May 2021

An event-related functional magnetic resonance imaging study examined how speakers inspect their own speech for errors. Concretely, we sought to assess 1) the role of the temporal cortex in monitoring speech errors, linked with comprehension-based monitoring; 2) the involvement of the cerebellum in internal and external monitoring, linked with forward modeling; and 3) the role of the medial frontal cortex for internal monitoring, linked with conflict-based monitoring. In a word production task priming speech errors, we observed enhanced involvement of the right posterior cerebellum for trials that were correct, but on which participants were more likely to make a word as compared with a nonword error (contrast of internal monitoring). Furthermore, comparing errors to correct utterances (contrast of external monitoring), we observed increased activation of the same cerebellar region, of the superior medial cerebellum, and of regions in temporal and medial frontal cortex. The presence of the cerebellum for both internal and external monitoring indicates the use of forward modeling across the planning and articulation of speech. Dissociations across internal and external monitoring in temporal and medial frontal cortex indicate that monitoring of overt errors is more reliant on vocal feedback control.
Gastrointestinal Manifestations of Pediatric Coronavirus Disease and Their Relationship with a Severe Clinical Course: A Systematic Review and Meta-analysis
Authors: Bolia Rishi , Dhanesh Goel Akhil , Badkur Mayank , Jain Vidhi
Published: May 2021

Background

Data on the gastrointestinal (GI) manifestations of Pediatric Corona Virus Disease (COVID-19) are conflicting and the relationship between GI involvement and the severity of COVID-19 disease has not been evaluated. The objectives of this systematic review were to determine the GI manifestations of pediatric COVID-19 and to evaluate their role as risk factors for a severe clinical course.

Methods

: A systematic literature search was carried out in PubMed and Scopus for studies published before 31 December 2020 with information about the GI manifestations of pediatric COVID-19. Patients with a severe and nonsevere clinical course were compared using the inverse variance heterogeneity model and odds ratio (OR) as the effect size. A sensitivity analysis was performed if the heterogeneity was high among studies.

Results

A total of 811 studies were identified through a systematic search of which 55 studies (4369 patients) were included in this systematic review. The commonest GI symptoms were diarrhea—19.08% [95% confidence interval (CI) 10.6–28.2], nausea/vomiting 19.7% (95% CI 7.8–33.2) and abdominal pain 20.3% (95% CI 3.7–40.4). The presence of diarrhea was significantly associated with a severe clinical course with a pooled OR of 3.97 (95% CI 1.80–8.73; p < 0.01). Abdominal pain and nausea/vomiting were not associated with disease severity.

Conclusions

Diarrhea, nausea/vomiting or abdominal pain are present in nearly one-fifth of all children with COVID-19. The presence of diarrhea portends a severe clinical course.
Levels of Evidence Supporting the North American and European Perioperative Care Guidelines for Anesthesiologists between 2010 and 2020: A Systematic Review
Authors: Laserna Andres , Rubinger Daniel A. , Barahona-Correa Julian E. , Wright Noah , Williams Mark R. , Wyrobek Julie A. , Hasman Linda , Lustik Stewart J. , Eaton Michael P. , Glance Laurent G.
Published: May 2021

Background

Although there are thousands of published recommendations in anesthesiology clinical practice guidelines, the extent to which these are supported by high levels of evidence is not known. This study hypothesized that most recommendations in clinical practice guidelines are supported by a low level of evidence.

Methods

A registered (Prospero CRD42020202932) systematic review was conducted of anesthesia evidence-based recommendations from the major North American and European anesthesiology societies between January 2010 and September 2020 in PubMed and EMBASE. The level of evidence A, B, or C and the strength of recommendation (strong or weak) for each recommendation was mapped using the American College of Cardiology/American Heart Association classification system or the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The outcome of interest was the proportion of recommendations supported by levels of evidence A, B, and C. Changes in the level of evidence over time were examined. Risk of bias was assessed using Appraisal of Guidelines for Research and Evaluation (AGREE) II.

Results

In total, 60 guidelines comprising 2,280 recommendations were reviewed. Level of evidence A supported 16% (363 of 2,280) of total recommendations and 19% (288 of 1,506) of strong recommendations. Level of evidence C supported 51% (1,160 of 2,280) of all recommendations and 50% (756 of 1,506) of strong recommendations. Of all the guidelines, 73% (44 of 60) had a low risk of bias. The proportion of recommendations supported by level of evidence A versus level of evidence C (relative risk ratio, 0.93; 95% CI, 0.18 to 4.74; P = 0.933) or level of evidence B versus level of evidence C (relative risk ratio, 1.63; 95% CI, 0.72 to 3.72; P = 0.243) did not increase in guidelines that were revised. Year of publication was also not associated with increases in the proportion of recommendations supported by level of evidence A (relative risk ratio, 1.07; 95% CI, 0.93 to 1.23; P = 0.340) or level of evidence B (relative risk ratio, 1.05; 95% CI, 0.96 to 1.15; P = 0.283) compared to level of evidence C.

Conclusions

Half of the recommendations in anesthesiology clinical practice guidelines are based on a low level of evidence, and this did not change over time. These findings highlight the need for additional efforts to increase the quality of evidence used to guide decision-making in anesthesiology.

Editor’s Perspective

What We Already Know about This Topic

What This Article Tells Us That Is New
CRYSTALENS REPOSITIONING WITH SCLERAL SUTURE TECHNIQUE
Authors: Smiddy William E.
Published: May 2021

Purpose:

To present a surgical technique that allows rescue (repositioning) of a dislocated Crystalens model intraocular lens using scleral sutures.

Methods:

The surgical technique is described with supplemental video.

Results:

The technique was used in one patient with 3 months of follow-up information. The intraocular lens was well-positioned, and the visual acuity is 20/20, without adverse events.

Conclusion:

Scleral suture techniques for repositioning of the Crystalens offer a suitable alternative to intraocular lens exchange.
Changing Nurse Practitioner Students' Attitudes and Beliefs About Caring for Those With Opioid Use Disorders
Authors: Elliott Kathleen M. , Chin Elizabeth , Gramling Kathryn Louise , Sethares Kristen A.
Published: May 2021

Purpose

Nurse practitioners (NPs) are in a unique position to address the problem of opioid use disorders (OUDs) because they provide a large percentage of primary care services (Agency for Healthcare Research and Quality, 2014). This study aimed to increase doctoral NP students' beliefs/attitudes about their ability to care for and about individuals with OUDs through a multifaceted educational approach, guided by social cognitive theory.

Methods

Researchers used a quasi-experimental pre/post design. Five doctoral students attended lectures and 16 hours of direct clinical exposure to individuals with OUDs at a medication-assisted treatment center. The 22-item Drug and Drug Problems Perception Questionnaire examined students' attitudes toward individuals with OUDs before and after receiving this multifaceted education. Students completed reflective writings. Descriptive statistics and effect sizes were computed, and reflective writings were reviewed.

Results

Changes in Drug and Drug Problems Perception Questionnaire scores before and after intervention showed a fairly large effect size. This suggests that the intervention may have clinical significance for practice and is likely to attain statistical significance with a larger sample size. Greatest changes occurred in students' perceptions of role adequacy and self-esteem scores, indicative of higher self-efficacy. Measured score increases correspond to increases in confidence, knowledge, and skills to therapeutically engage with this population.

Conclusion

Doctoral NP students had more positive attitudes and beliefs about individuals with OUDs after the multifaceted intervention. Enhancement of self-esteem and adequacy in the caregiver role for this population were promising signals that education can reduce stigma. Further study is warranted with a larger and more diverse sample.
The Missing Link
Authors: Danda Michelle C.
Published: May 2021

Harm reduction is becoming integrated into the hospital setting, yet there is a dearth of published academic literature on the topic of harm reduction in mental health nursing practice. No results were found in a literature search focused specifically on harm reduction policies in the inpatient psychiatric settings using the databases CINAHL, Google Scholar, and PubMed. The purpose of this article was to provide a historical overview of harm reduction in Canadian nursing from 1998 to 2018. The aim was to help direct care nurses, educators, and administrators understand past and present trends and to identify future possibilities for integration in inpatient mental health care. A historical perspective was used to identify and explore Canadian harm reduction literature published from 1998 to 2018 to establish the significance to inform nursing practice. The exploration began with a brief description of outreach nursing in early Canada. Focus shifted to the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic of the 1980s and 1990s, on to the 2000s when a broader lens of harm reduction was adopted, looking beyond the goal of reducing sexually transmitted illnesses. Literature published in the mid-2000s focused on marginalized populations, highlighting the connection between ethical practice and harm reduction philosophy. At the beginning of the 2010s, the Canadian Nursing Association released position statements that explicitly identified the role of harm reduction in nursing practice. Toward the end of the 2010s, the opioid overdose crisis promoted harm reduction nurses taking a broader focus, entering the hospital settings.
Situations That Lead Women to Seek Treatment for Drug Addiction
Authors: Moll Marciana F. , Santos Vanessa O. , Duarte Cleudiane F. , Silva Paulline S. , Ventura Carla A. A.
Published: May 2021

Introduction

Investigating the situations that lead women to seek treatment for drug addiction is necessary, as women experience the organic, social, and family damage caused by addiction intensely.

Objective

The aim of this study was to describe situations that lead women to seek treatment for drug addiction.

Method

This is an exploratory, descriptive study, with a qualitative approach, carried out in a CAPS Ad service in the state of Minas Gerais (CAAE: 92864518.4.0000.5145). Open interviews were conducted in September 2018 with 24 of 28 women assisted by the service. The discourse of the collective subject was the basis of the data analysis.

Results

Social, family, and health problems were the main damaging impact of drug addiction among the women and were represented by the following: death of loved ones, violence from partners, theft, cognitive problems, hypertension, and diabetes. Specifically, it was affective and material losses experienced during the period of addiction that led the women to seek treatment.

Final Considerations

It is necessary to facilitate women's access to treatment for drug addiction and to incorporate their families into the treatment through activities that will reinforce the former's commitment to any proposed therapeutics; in addition, goals to reconstruct bonds within the family environment should be established.
Residual SYNTAX II Score and long-term outcomes post-ST-elevation myocardial infarction in an urban US cohort: the Montefiore STEMI Registry
Authors: Bortnick Anna E. , Shitole Sanyog G. , Hashim Hayder , Khullar Pankaj , Park Michael , Weinreich Michael , Seibert Stephen , Rauch Judah , Weisz Giora , Kizer Jorge R.
Published: May 2021

Background

Higher residual anatomic disease was associated with increased mortality in a recent randomized controlled trial of revascularization after ST-elevation myocardial infarction (STEMI). Less is known about the impact of residual disease post-STEMI in race-ethnic minorities.

Methods

Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX)- II (SS-II) score is an established scoring method for anatomic disease and prevalent co-morbidities to describe patient complexity. We evaluated residual (r) SS-II in 165 patients from a single center urban US registry (n = 1208) presenting for primary percutaneous coronary intervention of STEMI and treated for 3-vessel or left main and any combination of 0, 1, 2 or 3-vessel disease.

Results

The median age was 62 years (IQR 52–70), 29.1% women, 44.9% Hispanic/Latino and 19.4% non-Hispanic Black. Over median of 4.9 years (IQR 2.9–6.3), higher rSS-II was associated with increased death [hazard ratio 2.46 per SD increment in log rSS-II (~five-fold increment on the original scale) 95% CI 1.51, 3.99], death or all-cause readmission (hazard ratio 1.37 per SD increment in log rSS-II 95% CI, 1.11–1.70) and death or cardiovascular disease readmission (hazard ratio 1.46 per SD increment in log rSS-II 95% CI, 1.14–1.88). rSS-II was higher in older women with more co-morbidities, but not different by race-ethnicity.

Conclusions

In summary, higher rSS-II was associated with long-term outcomes post-STEMI in a prospective urban, minority cohort, suggesting a potential role for risk stratification with this measure in a non-trial setting.
Performance Measurement Outcomes: An Analysis of Health Care–Associated Infections in New York State
Authors: Pitocco Christine , Lewis Herbert F. , Liu Jonathan
Published: May 2021

Background and Objectives:

Comparing outcome measures in health care is a relatively common practice. Reports are designed to compare hospital infection rates in an accurate and fair manner. The current methodology used by New York State (NYS) has some limitations and flaws. This research provides a methodology that overcomes these limitations and flaws.

Methods:

The methodology is a replication study using data from NYS and includes the use of the binomial and Poisson distribution to calculate upper tail (UTP) and lower tail probabilities (LTP). The UTP is used to screen for poor performers, and the LTP is used to screen for good performers.

Results:

The results we obtained using the tail probability method compared with NYS's confidence interval approach are similar across all health care–associated infection (HAI) categories but have the benefit of allowing for the analysis of any hospital regardless of the number of procedures, number of central line-days, or number of patient-days. In addition, we provide an evaluation of a hospital's performance over time where we identified hospitals that were consistently performing poorly and others consistently performing well.

Conclusion:

Identifying hospitals that are consistently performing poorly and hospitals consistently performing well will allow administrators and clinicians to focus their efforts including budgetary to where improvements are needed. Patient care and the reduction of HAIs are a priority for health care institutions. While the results are similar to those reported by NYS, this approach can be used more comprehensively and can be interpreted more easily by administrators and practitioners. Health care administrators and clinicians may find the information useful to address infection rates. Hospitals consistently performing well may be used as a benchmark.
A Rapid Guidance Process for the Development of an Anticoagulation Protocol in the COVID-19 Pandemic
Authors: Tremblay Douglas , Dunn Andrew S. , Oh William K.
Published: May 2021

Health care systems have encountered unprecedented challenges during the coronavirus disease-2019 (COVID-19) pandemic, such as standardizing care in the absence of high-quality data. As an emblematic example, preliminary data and early anecdotal experience suggested that a major driver of COVID-19 pathophysiology was hypercoagulability, suggesting the need for aggressive anticoagulation. In this article, we describe the rapid guidance process for the development of an anticoagulation protocol for COVID-19. Preliminary evidence was collected from multidisciplinary experts within our institution to inform the first protocol draft. After implementation, we rapidly acquired data to inform a revision, with subsequent modifications based on higher quality data. The description of this process can inform other health systems when faced with a similar crisis characterized by high patient volumes, poor clinical outcomes, lack of proven effective therapies, and rapid flow of information from multiple sources of variable credibility.
COVID-19 vaccination in California: Are we equitable yet?
Authors: Schmidt Alec J. , Daza-Torres Maria L. , García Yury E. , Ashby Joan L. , Pollock Bradley H. , Sharpnack James , Nuño Miriam
Published: May 2021

Background

By March 2021, California had one of the least equitable COVID-19 vaccine distribution programs in the US. To rectify this, Governor Newsom ordered 4 million vaccine doses be reserved for the census tracts in the lowest quartile of the Healthy Places Index (HPI). California plans to lift state-wide restrictions on June 15th, 2021, as long as test positivity and vaccine equity thresholds are met in the state’s most vulnerable neighborhoods. This short investigation examines current vaccine equity and forecasts where California can expect to be when the economy fully reopens.

Methods

Current vaccine equity was investigated with simple linear regression between the county mean HPI and both single and full-dose vaccination rate. Future vaccination coverage per county were predicted using a compartmental mathematical model based on the average rate over the previous 30 days with four different rate-change scenarios.

Results

County mean HPI had a strong positive association with both single and full dose vaccination rates (R2: 0.716 and 0.737, respectively). We predict the overall state rate will exceed 50% fully vaccinated by June 15th if the current rates are maintained; however, the bulk of this coverage comes from the top 18 counties while the remaining 40 counties lag behind.

Discussion

The clear association between county HPI and current vaccination rates shows that California is not initiating opening plans from an equitable foundation, despite previous equity programs. If nothing changes, many of the most vulnerable counties will not be prepared to open without consequences come June 15th.
A ratiometric dual-color luciferase reporter for fast characterization of transcriptional regulatory elements
Authors: González-Grandío E. , Demirer G. S. , Ma W. , Brady S.M. , Landry M.P.
Published: May 2021

Plant synthetic biology requires precise characterization of genetic elements to construct complex genetic circuits that can improve plant traits or confer them new characteristics. Transcriptional reporter assays are essential to quantify the effect of gene expression regulator elements. Therefore, transcriptional reporter systems are a key tool in understanding control of gene expression in biology.

In this work we construct and characterize a dual-color luciferase ratiometric reporter system that possesses several advantages over currently used reporters. It is ratiometric, reducing variability and increasing consistency between experiments; it is fast, as both reporters can be measured at the same time in a single reaction, and it is cheaper to perform than current dual-luciferase reporter assays. We have validated our system quantifying the transcriptional capability of a panel of promoters and terminators commonly used in synthetic biology with a broad range of expression magnitudes, and in a biologically relevant system, nitrate response.
KIR gene content imputation from single-nucleotide polymorphisms in the Finnish population
Authors: Ritari Jarmo , Hyvärinen Kati , Partanen Jukka , Koskela Satu
Published: May 2021

The killer cell immunoglobulin-like receptor (KIR) gene cluster on chromosome 19 encodes cell surface glycoproteins that bind class I human leukocyte antigen (HLA) molecules as well as some other ligands. Through regulation of natural killer (NK) cell activity KIRs participate in tumour surveillance and clearing viral infections. KIR gene gene copy number variation associates with the outcome of transplantations and susceptibility to immune-mediated diseases. Inferring KIR gene content from genetic variant data is therefore desirable for immunogenetic analysis, particularly in the context of growing biobank genome data collections that rely on genotyping by microarray. Here we describe a stand-alone and freely available gene content imputation for 12 KIR genes. The models were trained using 818 Finnish biobank samples genotyped for 5774 KIR-region SNPs and analysed for KIR gene content with targeted sequencing. Cross-validation results demonstrate a high mean overall accuracy of 99.2% (95% CI: 97.8-99.7%) which compares favourably with previous methods including short-read sequencing based approaches.
Coral: a web-based visual analysis tool for creating and characterizing cohorts
Authors: Adelberger Patrick , Eckelt Klaus , Bauer Markus J. , Streit Marc , Haslinger Christian , Zichner Thomas
Published: May 2021

A main task in computational cancer analysis is the identification of patient subgroups (i.e., cohorts) based on metadata attributes (patient stratification) or genomic markers of response (biomarkers). Coral is a web-based cohort analysis tool that is designed to support this task: Users can interactively create and refine cohorts, which can then be compared, characterized, and inspected down to the level of single items. Coral visualizes the evolution of cohorts and also provides intuitive access to prevalence information. Furthermore, findings can be stored, shared, and reproduced via the integrated session management. Coral is pre-loaded with data from over 128,000 samples from the AACR Project GENIE, The Cancer Genome Atlas, and the Cell Line Encyclopedia.

Availability and Implementation

Coral is publicly available at https://coral.caleydoapp.org. The source code is released at https://github.com/Caleydo/coral.

Contact

thomas.zichner@boehringer-ingelheim.com

Supplementary information

Supplementary data are available at Bioinformatics online.
Cingulate-motor circuits update rule representations for sequential choice decisions
Authors: Takeuchi Daigo , Roy Dheeraj , Muralidhar Shruti , Kawai Takashi , Lovett Chanel , Sullivan Heather A. , Wickersham Ian R. , Tonegawa Susumu
Published: May 2021

Anterior cingulate cortex mediates the flexible updating of an animal’s choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the projection terminals of cingulate cortical neurons in secondary motor cortex disrupted sequential choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreased rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that was temporally targeted to error trials immediately after rule switches exacerbated errors in following trials. These results suggest that cingulate cortex monitors behavioral errors and update rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.
Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab
Authors: Gupta Anil , Gonzalez-Rojas Yaneicy , Juarez Erick , Casal Manuel Crespo , Moya Jaynier , Falci Diego Rodrigues , Sarkis Elias , Solis Joel , Zheng Hanzhe , Scott Nicola , Cathcart Andrea L. , Hebner Christy M. , Sager Jennifer , Mogalian Erik , Tipple Craig , Peppercorn Amanda , Alexander Elizabeth , Pang Phillip S. , Free Almena , Brinson Cynthia , Aldinger Melissa , Shapiro Adrienne E. ,   for the COMET-ICE Investigators
Published: May 2021

Background

Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody designed to treat such high-risk patients early in the course of disease, thereby preventing Covid-19 progression.

Methods

In this ongoing, multicenter, double-blind, phase 3 trial, nonhospitalized patients with symptomatic Covid-19 and at least one risk factor for disease progression were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with Covid-19 progression, defined as hospitalization longer than 24 hours or death, through day 29.

Results

In this preplanned interim analysis, which included an intent-to-treat population of 583 patients (sotrovimab, 291; placebo, 292), the primary efficacy endpoint was met. The risk of Covid-19 progression was significantly reduced by 85% (97.24% confidence interval, 44% to 96%; P = 0.002) with a total of three (1%) patients progressing to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group. All five patients admitted to intensive care, including one who died by day 29, received placebo. Safety was assessed in 868 patients (sotrovimab, 430; placebo, 438). Adverse events were reported by 17% and 19% of patients receiving sotrovimab and placebo, respectively; serious adverse events were less common with sotrovimab (2%) versus placebo (6%).

Conclusion

Sotrovimab reduced progression of Covid-19 in patients with mild/moderate disease, was well tolerated, and no safety signals were identified.

Funded by Vir Biotechnology, Inc. and GlaxoSmithKline; ClinicalTrials.govNCT04545060
Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest
Authors: Adams Anngela C. , Macy Anne M. , Kang Paul , Castro-Ochoa Karla F. , Wijeratne E. M. Kithsiri , Xu Ya-Ming , Liu Manping X. , Charos Alexandra , Bosenberg Marcus W. , Gunatilaka A. A. Leslie , Sertil Aparna R. , Hastings K. Taraszka
Published: May 2021

Melanoma is an aggressive skin cancer that metastasizes to other organs. While immune checkpoint blockade with anti-PD-1 has transformed the treatment of advanced melanoma, many melanoma patients fail to respond to anti-PD-1 therapy or develop acquired resistance. Thus, effective treatment of melanoma still represents an unmet clinical need. Our prior studies support the anti-cancer activity of the 17β-hydroxywithanolide class of natural products, including physachenolide C (PCC). As single agents, PCC and its semi-synthetic analog demonstrated direct cytotoxicity in a panel of murine melanoma cell lines, which share common driver mutations with human melanoma; the IC50 values ranged from 0.18 – 1.7 µM. PCC treatment induced apoptosis of tumor cells both in vitro and in vivo. In vivo treatment with PCC alone caused the complete regression of established melanoma tumors in all mice, with a durable response in 33% of mice after discontinuation of treatment. T cell-mediated immunity did not contribute to the therapeutic efficacy of PCC or prevent tumor recurrence in YUMM2.1 melanoma model. In addition to apoptosis, PCC treatment induced G0-G1 cell cycle arrest of melanoma cells, which upon removal of PCC, re-entered the cell cycle. PCC-induced cycle cell arrest likely contributed to the in vivo tumor recurrence in a portion of mice after discontinuation of treatment. Thus, 17β-hydroxywithanolides have the potential to improve the therapeutic outcome for patients with advanced melanoma.
Graminoids vary in functional traits, carbon dioxide and methane fluxes in a restored peatland: implications for modeling carbon storage
Authors: Goud Ellie M. , Touchette Sabrina , Strachan Ian B. , Strack Maria
Published: May 2021

One metric of peatland restoration success is the re-establishment of a carbon sink, yet considerable uncertainty remains around the timescale of carbon sink trajectories. Conditions post-restoration may promote the establishment of vascular plants such as graminoids, often at greater density than would be found in undisturbed peatlands, with consequences for carbon storage. Although graminoid species are often considered as a single plant functional type (PFT) in land-atmosphere models, our understanding of functional variation among graminoid species is limited, particularly in a restoration context. We used a traits-based approach to evaluate graminoid functional variation and to assess whether different graminoid species should be considered a single PFT or multiple types. We tested hypotheses that greenhouse gas fluxes (CO2, CH4) would vary due to differences in plant traits among five graminoid species in a restored peatland in central Alberta, Canada. We further hypothesized that species would form two functionally distinct groupings based on taxonomy (grass, sedge). Differences in gas fluxes among species were primarily driven by variation in leaf physiology related to photosynthetic efficiency and resource-use, and secondarily by plant size. Multivariate analyses did not reveal distinct functional groupings based on taxonomy or environmental preferences. Rather, we identified functional groups defined by continuous plant traits and carbon fluxes that are consistent with ecological strategies related to differences in growth rate, resource-acquisition, and leaf economics. These functional groups displayed larger carbon storage potential than currently-applied graminoid PFTs. Existing PFT designations in peatland models may be more appropriate for pristine or high-latitude systems than those under restoration. Although replacing PFTs with continuous plant traits remains a challenge in peatlands, traits related to leaf physiology and growth rate strategies offer a promising avenue for future applications.
Density-based binning of gene clusters to infer function or evolutionary history using GeneGrouper
Authors: McFarland Alexander G. , Kennedy Nolan W. , Mills Carolyn E. , Tullman-Ercek Danielle , Huttenhower Curtis , Hartmann Erica M.
Published: May 2021

Motivation

Identifying gene clusters of interest in phylogenetically proximate and distant taxa can help to infer phenotypes of interest. Conserved gene clusters may differ by only a few genes, which can be biologically meaningful, such as the formation of pseudogenes or insertions interrupting regulation. These qualities may allow for unsupervised clustering of similar gene clusters into bins that provide a population-level understanding of the genetic variation in similar gene clusters.

Results

We developed GeneGrouper, a command-line tool that uses a density-based clustering method to group gene clusters into bins. GeneGrouper demonstrated high recall and precision in benchmarks for the detection of the 23-gene Salmonella enterica LT2 Pdu gene cluster and four-gene Pseudomonas aeruginosa PAO1 Mex gene cluster in 435 genomes containing mixed taxa. In a subsequent application investigating the diversity and impact of gene complete and incomplete LT2 Pdu gene clusters in 1130 S. enterica genomes, GeneGrouper identified a novel, frequently occurring pduN pseudogene. When replicated in vivo, disruption of pduN with a frameshift mutation negatively impacted microcompartment formation. We next demonstrated the versatility of GeneGrouper by clustering both distant homologous gene clusters and variable gene clusters found in integrative and conjugative elements.

Availability

GeneGrouper software and code are publicly available at https://github.com/agmcfarland/GeneGrouper.
Structure Learning for Hierarchical Regulatory Networks
Authors: Federico Anthony , Kern Joseph , Varelas Xaralabos , Monti Stefano
Published: May 2021

Network analysis offers a powerful technique to model the relationships between genes within biological regulatory networks. Inference of biological network structures is often performed on high-dimensional data, yet is hindered by the limited sample size of high throughput “omics” data typically available. To overcome this challenge, we exploit known organizing principles of biological networks that are sparse, modular, and likely share a large portion of their underlying architecture. We presentSHINE-Structure Learning forHierarchicalNetworks - a framework for defining data-driven structural constraints and incorporating a shared learning paradigm for efficiently learning multiple networks from high-dimensional data. We show through simulationsSHINEimproves performance when relatively few samples are available and multiple networks are desired, by reducing the complexity of the graphical search space and by taking advantage of shared structural information. We evaluatedSHINEon TCGA Pan-Cancer data and found learned tumor-specific networks exhibit expected graph properties of real biological networks, recapture previously validated interactions, and recapitulate findings in literature. Application ofSHINEto the analysis of subtype-specific breast cancer networks identified key genes and biological processes for tumor maintenance and survival as well as potential therapeutic targets for modulating known breast cancer disease genes.
Circulatory systems and mortality rates
Authors: Uppal Gurdip , Zorlutuna Pinar , Vural Dervis Can
Published: May 2021

Aging is a complex process involving multiple factors and subcellular processes, ultimately leading to the death of an organism. The microscopic processes that cause aging are relatively well understood and effective macroscopic theories help explain the universality of aging in complex systems. However, these theories fail to explain the diversity of aging observed for various lifeforms. As such, more complete “mesoscopic” theories of aging are needed, combining the biophysical details of microscopic failure and the macroscopic structure of complex systems. Here we explore two models: (1) a network theoretic model, and (2) a convection diffusion model emphasizing the biophysical details of communicated signals. The first model allows us to explore the effects of connectivity structures on aging. In our second model, cells interact through cooperative and antagonistic factors. We find by varying the ratio at which these factors affect cell death, as well as the reaction kinetics, diffusive and flow parameters, we obtain a wide diversity of mortality curves. As such, the connectivity structures as well as the biophysical details of how various factors are transported in an organism may explain the diversity of aging observed across different lifeforms.
Feasibility of an Inhalable Ultrasound Contrast Agent to Enhance Airway Imaging
Authors: Clapp Phillip W. , Durham Phillip G. , Antinori Jamie C. , Walmer Rachel W. , Chlebowski Jessica G. , Velasco Brian , Snow Samantha J. , Dayton Paul A. , Caughey Melissa C.
Published: May 2021

Introduction

Ultrasound is a relatively inexpensive and non-ionizing imaging modality, but is under-utilized in large airway assessments due to poor image quality. No commercially available contrast agents currently exist for sonographic evaluation of the respiratory system, nor has a respiratory route of microbubble contrast agent (MCA) administration been previously described for the enhancement of airway imaging.

Methods

We conducted a feasibility study to assess proof-of-concept for an inhalable ultrasound MCA composed of lipid-encapsulated decaflourobutane gas. The MCA was nebulized and administered as an aerosol through the lumen of an ex vivo porcine trachea, with image enhancement evaluated by comparing images pre- and post-exposure. Additionally, primary human bronchial epithelial (hBE) cells from three donors were differentiated at an air-liquid interface and exposed apically to 25 μL of undiluted MCA or vehicle control to assess contrast agent-induced cytotoxicity and inflammation. Basolateral medium was collected 24-hours post-exposure and lactate dehydrogenase (LDH) and interleukin-8 (IL-8) concentrations were measured as biomarkers of cytotoxicity and inflammation, respectively.

Results

Contrast microbubbles remained intact following nebulization and enhanced sonographic delineation of ex vivo porcine tracheal walls, indicating adherence of the nebulized MCA to the lumenal mucosa. No significant cytotoxic or inflammatory effects were observed in cultured hBE cells following exposure to MCA.

Conclusions

We present proof-of-concept for an inhaled MCA for the enhancement of sonographic evaluations of the large airways. Pending further evaluations for safety and effectiveness, inhaled MCA may be feasible for clinical ultrasound applications, such as enhancing ultrasound-guided tracheal intubation, detecting airway bleeds, or monitoring large airway diseases in pediatric populations.
Multi-dimensional analyses identify genes of high priority for pancreatic cancer research
Authors: Nwosu Zeribe C. , Giza Heather , Nassif Maya , Charlestin Verodia , Menjivar Rosa E. , Kim Daeho , Kemp Samantha B. , Steele Nina G. , Hu Jiantao , Hu Biao , Wang Shaomeng , Pasca di Magliano Marina , Lyssiotis Costas A.
Published: May 2021

Genomic profiling has unveiled the molecular subtypes and mutational landscape of pancreatic ductal adenocarcinoma (PDAC). However, there is a knowledge gap on the consistency of gene expression across PDAC tumors profiled in independent studies and this limits follow up research. To facilitate novel drug target prioritization and biomarker discovery, we investigated the most consistently expressed genes in human PDAC. We identified ~4,000 genes highly or lowly expressed in at least 4 of 5 microarrays (adjusted P<0.05) and validated their expression pattern in additional datasets, bulk tumor and single-cell RNA sequencing samples. Over 50% of the genes were previously uncharacterized in PDAC; many correlated with proliferation, metastasis, mutation, tumor grade, and ~41% predicted overall survival. We identified 185 high-priority targets (notably in cell cycle and glycolysis) whose inhibition suppressed PDAC cell viability in multiple RNA interference datasets and these genes predicted treatment in mouse models. Our results represent important milestone in the quest for mechanisms, drug targets and biomarkers in PDAC, and originate from an adaptable analytical concept that can aid discovery in other cancers.

Highlights

Identifies ~4,000 consistent genes across PDAC microarrays, >50% of which have not been studied

Glycolysis and cell cycle are the most consistent processes in PDAC

Heterogeneous pathways underlie or correlate with clinicopathological variables

Identifies 205 genes with similar expression pattern in PDAC tissues and peripheral blood

Highlights 185 upregulated genes that are high priority therapeutic targets in PDAC
Pro-regenerative Extracellular Matrix Hydrogel Prevents and Mitigates Pathological Alterations of Pelvic Muscles Following Birth Injury
Authors: Duran Pamela , Sesillo Francesca Boscolo , Burnett Lindsey , Menefee Shawn A. , Cook Mark , Zazueta-Damian Gisselle , Dzieciatkowska Monika , Do Emmy , French Saya , Shah Manali M. , Sanvictores Clyde , Hansen Kirk C. , Shtrahman Matthew , Christman Karen L. , Alperin Marianna
Published: May 2021

Pelvic floor disorders, which include pelvic organ prolapse, and urinary and fecal incontinence, affect millions of women globally and represent a major public health concern. Pelvic floor muscle (PFM) dysfunction has been identified as one of the leading risk factors for the development of these morbid conditions. Even though childbirth, specifically vaginal delivery, has been long recognized as the most important potentially modifiable risk factor for PFM injury, the precise mechanisms of PFM dysfunction following childbirth remain elusive. In this study we demonstrate that PFMs undergo atrophy and severe fibrosis in parous women with symptomatic pelvic organ prolapse compared to age-matched nulliparous cadaveric donors without history of pelvic floor disorders. These pathological alterations are recapitulated in the pre-clinical rat model of simulated birth injury. The transcriptional signature of PFMs post-injury demonstrates a sustained inflammatory response, impairment in muscle anabolism, and persistent expression of extracellular matrix (ECM) remodeling genes. Next, we evaluated the administration of acellular injectable skeletal muscle extracellular matrix hydrogel for the prevention and mitigation of these pathological alterations. Treatment of PFMs with the biomaterial either at the time of birth injury or 4 weeks post-injury reduced muscle atrophy and mitigated fibrotic degeneration. By evaluating gene expression, we demonstrate that these changes are mainly driven by the hydrogel-induced modulation of the immune response and intramuscular fibrosis, as well as enhancement of the endogenous myogenesis. This work furthers our understanding of PFM birth injury and demonstrates proof-of-concept for a new pragmatic pro-regenerative biomaterial approach for treating injured PFMs.
Aerosol-based ligand soaking of reservoir-free protein crystals
Authors: Ross Breyan , Krapp Stephan , Geiss-Friedlander Ruth , Littmann Walter , Huber Robert , Kiefersauer Reiner
Published: May 2021

Soaking of macromolecular crystals allows the formation of complexes via diffusion of molecules into a preformed crystal for structural analysis. Soaking offers various advantages over co-crystallization, e.g. small samples and high-throughput experimentation. However, this method has disadvantages, such as inducing mechanical stress on crystals and reduced success rate caused by low affinity/solubility of the ligand. To bypass these issues, the Picodropper was previously developed in the authors' laboratory. This technique aimed to deliver small volumes of compound solution in response to crystal dehydration supported by the Free Mounting System humidity control or by IR-laser-induced protein crystal transformation. Herein, a new related soaking development, the Aerosol-Generator, is introduced. This device delivers compounds onto the solution-free surface of protein crystals using an ultrasonic technique. The produced aerosol stream enables an easier and more accurate control of solution volumes, reduced crystal handling, and crystal-size-independent soaking. The Aerosol-Generator has been used to produce complexes of DPP8 crystals, where otherwise regular soaking did not achieve complex formation. These results demonstrate the potential of this device in challenging ligand-binding scenarios and contribute to further understanding of DPP8 inhibitor binding.