bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Update for Physical Therapists: Coagulopathy and COVID-19
Authors: Lukaszewicz Kathleen , Hillegass Ellen , Puthoff Michael L , MacPhedran A Kate
Published: September 2020

Physical therapists have a unique role in both prevention of venous thromboembolism (VTE) through the promotion of early mobility and physical activity and diagnosis through discovery of signs and symptoms of VTE. This Perspective updates clinicians on the latest information regarding pathophysiology of coagulopathy associated with COVID-19 and applies VTE clinical practice guidelines to COVID-19 in order to provide guidance on physical therapist management.
Seasonal Dynamics of Core Fungi in the Switchgrass Phyllosphere, and Co-Occurrence with Leaf Bacteria
Authors: Bowsher Alan W. , Benucci Gian Maria Niccolò , Bonito Gregory , Shade Ashley
Published: September 2020

Plant leaves harbor complex microbial communities that influence plant health and productivity. Nevertheless, a detailed understanding of phyllosphere community assembly and drivers is needed, particularly for phyllosphere fungi. Here, we investigated seasonal dynamics of epiphytic phyllosphere fungal communities in switchgrass (Panicum virgatum L.), a focal bioenergy crop. We also leverage previously published data on switchgrass phyllosphere bacterial communities from the same experimental plants, allowing us to compare fungal and bacterial dynamics and explore interdomain network associations in the switchgrass phyllosphere. Overall, we found a strong impact of sampling date on fungal community composition, with multiple taxonomic levels exhibiting clear temporal patterns in relative abundance. In addition, leaf nitrogen concentration, leaf dry matter content, plant height, and minimum daily air temperature explained significant variation in phyllosphere fungal communities, likely due to their correlation with sampling date. Finally, among the core taxa, fungi–bacteria network associations were much more common than bacteria–bacteria associations, suggesting the importance of interdomain phylogenetic diversity in microbiome assembly. Although our findings highlight the complexity of phyllosphere microbiome assembly, the clear temporal patterns in lineage-specific fungal abundances give promise to the potential for accurately predicting shifts in fungal phyllosphere communities throughout the growing season, a key research priority for sustainable agriculture.

[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Biologic therapies for systemic lupus erythematosus: where are we now?
Authors: Murphy Grainne , Isenberg David A.
Published: September 2020

Purpose of review

Conventional approaches using hydroxychloroquine, corticosteroids and immunosuppressives have improved the prognosis for systemic lupus erythematosus (SLE) patients. Unfortunately, they have reached the limits of what they can achieve and patients still die prematurely and/or find their quality of life greatly impaired. Here, we discuss the problems of assessing activity in SLE, optimizing clinical trial design and more recent biologic approaches.

Recent findings

The success of B-cell depletion using Rituximab in open clinical studies, the approval of Belimumab (blocks the B-cell activating factor BAFF) and improvements in clinical trial design, gives cause for hope. Approaches including the use of fully humanized anti-CD20 and CD19 monoclonals, blocking interferons, inhibiting Bruton's tyrosine kinase (BTK), blocking the CD40 ligand (CD40L), utilizing an analogue of the FcɣRIIB and an IL12-23 blocker and targeting the JAK-STAT pathway have met end points in phase II and III trials.

For 20 years, we hoped that the successes of the biologic therapies in rheumatoid arthritis and psoriatic arthritis would be replicated in SLE but we have been generally disappointed. However, the encouraging recent results with monoclonals that block interferon and fully humanized anti-CD20 in particular, offer the prospect of a real revolution in the treatment of SLE.
Detection, screening, and classification of interstitial lung disease in patients with systemic sclerosis
Authors: Hoffmann-Vold Anna-Maria , Molberg Øyvind
Published: September 2020

Purpose of review

Interstitial lung disease (ILD) associates with disease burden and reduced life expectancy in systemic sclerosis (SSc). As ILD afflicts around 50% of SSc patients and is often present from early on, there is rationale for early and universal ILD screening. With the approval of the first SSc-ILD therapy last year, there is an increasing need for ILD classifications to assign the right treatment to the right patient. Here, we discuss recent advances on screening, detection, and classification of SSc-ILD.

Recent findings

Although prospective datasets from a nationwide population-based SSc cohort confirm insufficient sensitivity of pulmonary function tests (PFTs) for ILD screening, they provide strong support for lung high resolution computed tomography (HRCT) as the primary tool to detect ILD. Lung ultrasound shows promise as an additional screening tool. Interpreting statements from a new European consensus on SSc-ILD management, we propose an urgent need for integrated SSc classification, grading ILD severity at time of diagnosis and evaluate risk for ILD progression. We discuss advances on potential parameters for such classification, including PFTs, quantitative HRCT analyses, patient-reported outcome measures, functional exercise capacity tests, and soluble biomarkers.

Early screening to diagnose ILD is feasible. With new therapies at hand, there is a need for integrated ILD classification including severity grading and risk for progression.
The Optimal Timing of Hydrogel Injection for Treatment of Intervertebral Disc Degeneration
Authors: Liu Zhiguo , Li Jianwen , Hu Minghsien , Wang Xiaoshuai , Chen Ningning , Cui Shangbin , Li Songbo , Liu Hanzhong , Chen Guoliang , Pan Ximin , Sun Haixing , Liu Shaoyu , Wei Fuxin
Published: September 2020

Study Design.

Animal experimental study.

Objective.

The aim of this study was to investigate the optimal time of hydrogel injection for regenerating intervertebral disc degeneration (IDD) based on T1ρ magnetic resonance imaging (MRI).

Summary of Background Data.

Currently, different approaches are being pursued to regenerate the IDD. However, the optimal timing for the regenerative intervention is unclear.

Methods.

The slowly, progressive IDD models were established in 18 rhesus monkeys. On the basis of the MR T1ρ values of the discs, the rhesus monkeys were divided into severe (T1ρ values: <81 ms), moderate (T1ρ values: 81∼95 ms), and mild (T1ρ values: 96∼110 ms) degeneration groups. Biocompatible hydrogel was injected into the central part of the nucleus pulposus of the discs under fluoroscopic guidance. Treatment effects were investigated using radiography, T1ρ MRI, and histology until 12 months postoperatively.

Results.

After injection, the T1ρ values of all the discs increased significantly at 1 month postoperatively, and then remained at approximately 110 ms in the mild and moderate groups during the whole observation period, with no significant difference compared to the values at 1 month (P > 0.05). However, in the severe group, the T1ρ values decreased significantly after 1 month and leveled at approximately 70 ms after 6 months, with significant difference compared to the values at 1 month (P < 0.05). In the mild and moderate groups, there were no significant differences between preoperative histological scores and those at 12 months (P > 0.05). However, the histological score in the severe group at 12 months was significantly higher than the preoperative scores (P < 0.05).

Conclusion.

This study suggested that the moderate degenerative stage of IDD (T1ρ values from 95 to 80 ms) could be the optimal time for hydrogel injection aimed at the regenerative intervention, based on T1ρ-MR imaging technique and quantitative analysis.

Level of Evidence: N/A
Molecular alterations in meningioma: prognostic and therapeutic perspectives
Authors: Birzu Cristina , Peyre Matthieu , Sahm Felix
Published: September 2020

Purpose of review

To discuss recent advances in the meningioma biology and their clinical implications.

Recent findings

Meningioma is the most common primary intracranial tumor. Mostly benign, 20% of cases display an aggressive behavior despite best standard of care. The genetic landscape of meningiomas is divided according toNF2mutational status. Although about 60% of meningiomas displayNF2mutations, the other share is more heterogenous. Mutations inTRAF7,SMO, v-akt murine thymoma viral oncogene homolog 1 (AKT1), PI3KCAandKLF4are seen mostly in WHO grade 1 meningiomas. In higher grade meningiomas, mutations of theTERTpromoter and deletions ofCDKN2A/Bemerge and have prognostic value. Moreover, mutations inDMD,BAP1andPBRM1have recently been discovered and are being further explored. DNA methylation subgroups offer valuable insight into meningioma prognosis and its implementation in clinical setting is under evaluation. Moreover, the study of distinct meningioma populations such as radiation-induced meningioma and progestin-associated meningioma may provide further insight into meningioma oncogenesis and potential therapeutic targets.

The mutational landscape of meningioma has expanded following the use of the new genetic sequencing approaches. Novel mutations have been characterized and reveal their prognostic and therapeutic applications. This improved understanding of meningioma biology has promising implications for novel treatment strategies.
Interprofessional Collaboration Improves Uptake of Flu Vaccines on a College Campus
Authors: Hargrave Kristi
Published: September 2020

In spite of an increased risk of transmission of influenza on college campuses, only 20% or fewer of college students in the United States receive the flu vaccine. This project evaluated an existing university program for flu vaccination, resulting in a collaboration pilot program in which a pharmacy conducted a mobile health clinic on campus. The percentage of students who obtained a flu vaccine from this initiative rose from about 4% to 9.46%, a 131% increase over the historical average.
Iridocorneal Angle Assessment After Laser Iridotomy With Swept-source Optical Coherence Tomography
Authors: Meduri Enrico , Gillmann Kevin , Bravetti Giorgio E. , Niegowski Letitia J. , Mermoud André , Weinreb Robert N. , Mansouri Kaweh
Published: September 2020

Aim:

To investigate the reliability of anterior chamber angle (ACA) measurements in narrow angles and assess the effect of laser peripheral iridotomy (LPI) on these measurements using novel swept-source optical coherence tomography (SS-OCT) technology.

Materials and Methods:

In this prospective observational study, patients with gonioscopically narrow angles were enrolled and scheduled for prophylactic LPI. Twelve ACA sections were obtained in each eye using SS-OCT (ANTERION, Heidelberg Engineering, Germany) before and after Nd:YAG LPI. A built-in algorithm calculated ACA measurements after manual identification of the scleral spur and ACA recess. Eight ACA parameters were evaluated: ACA (ACA 500, ACA 750); scleral spur angle (SSA 500, SSA 750); angle opening distance (AOD 500, AOD 750); and trabecular iris space area (TISA 500, TISA 750). The effect of LPI was assessed for each parameter, both nasally and temporally.

Results:

Ten patients (18 eyes) were enrolled (mean age, 61.8±13.6 y; 60.0% female individuals). On average, the ACA was wider nasally than temporally (P=0.004). LPI significantly widened the ACA (range, 26.7-29.4%; P<0.05). ACA 500 increased by 29.4% (P<0.001), ACA 750 by 29.2% (P=0.002), SSA 500 by 27.3% (P=0.003), SSA 750 by 28.1% (P=0.001), AOD 500 by 28.6% (P=0.009), AOD 750 by 28.6% (P=0.003), TISA 500 by 27.3% (P=0.004), and TISA 750 by 26.7% (P=0.200).

Conclusions:

SS-OCT ANTERION imaging can be used to reliably measure ACA before and after LPI. ACA, AOD, SSA, and TISA are all valid ACA measurement methods.
Lower Eyelid Horizontal Tightening in Prostaglandin Associated Periorbitopathy
Authors: Procianoy Fernando , P.L. Lang Martha , J.L. Bocaccio Francisco
Published: September 2020

Purpose:

To determine the effect of chronic topical use of prostaglandin analogs for glaucoma on lower eyelid tension.

Methods:

A prospective case–control study was performed. Lower eyelid tension was measured in a group of glaucoma patients (73 eyelids) using prostaglandin analogs and a paired control group (87 eyelids). Seven glaucoma patients with unilateral use of prostaglandin analogs had the lower eyelid tension of the exposed side compared with the contralateral eyelid. Eyelid tension was digitally measured in photographs in neutral position and after manual downward traction in the center of the eyelid (modified distraction test). Duration of drug exposition, age, use of other topical medication and other prostaglandin-associated periorbitopathy signs as long eyelashes, eyelid hyperemia, eyelid pigmentation, and deepening of upper eyelid sulcus were recorded for analysis.

Results:

Mean lower eyelid tension in prostaglandin group was significantly higher than in control group: distraction 5.26 mm (SD 1.52) versus 6.80 mm (SD 1.29) (p < 0.001). On the unilateral prostaglandin use intragroup comparison, mean lower eyelid distraction in prostaglandin side was 4.24 mm (SD 1.80) and in control side was 6.79 mm (SD 1.63) (p < 0.012). Beta blocker and carbonic anhydrase inhibitor concomitant use was associated with lower eyelid tension measures in prostaglandin users. Presence of long eyelashes was associated with higher eyelid tension. All other measured variables did not demonstrate interaction with eyelid tension.

Conclusions:

Chronic topical use of prostaglandin analogs for glaucoma is associated with lower eyelid tightening.
Does gender matter: sex-specific aspects of symptoms, outcome, and therapy of obstructive sleep apnea
Authors: Schiza Sophia E. , Bouloukaki Izolde
Published: September 2020

Purpose of review

Obstructive sleep apnea (OSA) has historically been considered as a male disease. As a result, female individuals with OSA were often under-diagnosed and under-treated compared with male individuals. However, recent data suggest that several OSA-associated adverse cardiovascular outcomes are more pronounced in women.

Recent findings

This review provides a summary of the most relevant recent evidence with regard to sex-specific OSA characteristics, including atypical symptoms, greater quality of life impairment and several more pronounced adverse outcomes in female individuals compared with male individuals. It also provides updated evidence on the influence of female gender on under-treatment of OSA with limited evidence supporting gender differences in the effects of OSA treatment.

There is evidence suggesting gender-based differences in the frequency, severity, clinical presentation, and outcomes of OSA. The recognition of these gender differences could improve screening with development of female-specific screening instruments, early diagnosis, and individualized therapeutic plans towards better disease management and its outcomes.
Novosphingobium ovatum sp. nov., isolated from a freshwater mesocosm
Authors: Chen Wen-Ming , Cai Cheng-Ye , Sheu Der-Shyan , Tsai Jyh-Ming , Sheu Shih-Yi
Published: September 2020

A bacterial strain, designated FSY-8T, was isolated from a freshwater mesocosm in Taiwan and characterized using the polyphasic taxonomy approach. Cells of strain FSY-8T were aerobic, Gram-stain-negative, rod-shaped, non-motile and formed yellow coloured colonies on Reasoner's 2A agar. Growth occurred at 20–40 °C (optimum, 30–37 °C) and pH 5–7 (optimum, pH 6) and in the presence of 0–0.5 % NaCl (optimum, 0 %, w/v). The major fatty acids (>10 %) of strain FSY-8T were summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c) and summed feature 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c). The polar lipid profile consisted of a mixture of phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, phosphatidylmonomethylethanolamine, phosphatidyldimethylethanolamine, sphingoglycolipid, diphosphatidylglycerol, an uncharacterized aminophospholipid, an uncharacterized glycolipid and an uncharacterized lipid. The major polyamine was spermidine. The major isoprenoid quinone was Q-10. The DNA G+C content was 64.8 mol %. Phylogenetic analyses based on 16S rRNA gene sequences and coding sequences of 92 protein clusters indicated that strain FSY-8T formed a phylogenetic lineage in the genus

Novosphingobium

. Strain FSY-8T showed 71.6–77.2 % average nucleotide identity and 19.9–22.8 % digital DNA–DNA hybridization identity with the strains of other

Novosphingobium

species. On the basis of phenotypic and genotypic properties and phylogenetic inference, strain FSY-8T should be classified in a novel species of the genus

Novosphingobium

, for which the name Novosphingobium ovatum sp. nov. is proposed. The type strain is FSY-8T (=BCRC 81051T=LMG 30053T=KCTC 52812T).
Arthrobacter mobilis sp. nov., a novel actinobacterium isolated from Cholistan desert soil
Authors: Ye Jing-Jing , Liu Shao-Wei , Lu Qin-Pei , Cheema Mohsin Tassawar , Abbas Muhammad , Sajid Imran , Huang Da-Lin , Sun Cheng-Hang
Published: September 2020

A Gram-stain-positive, aerobic, catalase-positive, oxidase-negative, non-mycelium-forming, motile, rod-shaped with one polar flagellum actinobacterium, designated E918T, was isolated from a desert soil collected in Cholistan desert, Pakistan. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain E918T belonged to the genus

Arthrobacter

and was most closely related to

Arthrobacter deserti

CGMCC 1.15091T (97.2 % similarity). The peptidoglycan was of the A3α type and the whole-cell sugar profile was found to contain galactose. The major menaquinone was MK-9(H2). The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and two unidentified glycolipids. The major fatty acids identified were anteiso-C15 : 0 and anteiso-C17 : 0. The G+C content of the genomic DNA was 68.69 mol%. The digital DNA–DNA hybridization and average nucleotide identity values between strain E918T and

A. deserti

CGMCC 1.15091T were 28.0 and 83.4%, respectively. On the basis of its phylogenetic, phenotypic and chemotaxonomic features, strain E918T was considered to represent a novel species of the genus

Arthrobacter

, for which the name Arthrobacter mobilis sp. nov. is proposed. The type strain of Arthrobacter mobilis is E918T (=JCM 33392T=CGMCC 1.16978T).
Wocania indica gen. nov., sp. nov., isolated from deep sea hydrothermal sulfide in the northwest Indian Ocean, and proposal to reclassify Flaviramulus ichthyoenteri as Wocania ichthyoenteri comb. nov.
Authors: He Yang , Zeng Xiang , Xiong Jinbo , Lai Qiliang , Li Jianyang , Shao Zongze
Published: September 2020

A novel Gram-stain-negative, non-motile, strictly aerobic, rod-shaped bacterium was isolated from deep-sea hydrothermal sulfide in the northwest Indian Ocean Ridge and designated as strain IOP_32T. Strain IOP_32Tcould grow at 4–40 °C (optimum, 37 °C), pH 5–9 (optimum, pH 7–8) and salinity of 0–12 % NaCl (w/v; optimum, 2–3 %). The 16S rRNA gene sequence of strain IOP_32Tis most similar toBizionia fulviaeEM7T,Bizionia berychisRA3-3-1T,Bizionia paragorgiaeKMM 6029TandOceanihabitans sediminisS9_10Twith 95.5–95.3 % similarity. The phylogenomic analysis indicated that strain IOP_32Tforms a distinct lineage withFlaviramulus ichthyoenteriTh78Twithin the familyFlavobacteriaceae. The average nucleotide identity, average amino acid identity and percentage of conserved protein values between strain IOP_32Tand the type strains of close genera were 72.3–78.5 %, 67.4−76.9 % and 56.3−61.6 %, respectively. The major cellular fatty acid was anteiso-C15 : 0. The respiratory quinone was MK-6. The polar lipids were mainly composed of phosphatidylethanolamine, an unidentified aminophospholipid and five unidentified polar lipids. Strain IOP_32Tis significantly different from related genera, which is reflected by the wide adaptability to temperature and salinity levels, the composition of phospholipids and fatty acids, and the results of phylogenetic analyses. The phenotypic properties and phylogenetic data suggest that the lineage represents a novel genus and species within the familyFlavobacteriaceae, for which the nameWocania indicagen. sp. nov. is proposed, with the type strain IOP_32T(=MCCC 1A14017T=KCTC 62660T). We also propose the reclassification ofFlaviramulus ichthyoenteriasWocania ichthyoentericomb. nov. (Th78T=DSM 26285T=JCM 18634T=KCTC 32142T).
TERT promoter mutation analysis for blood-based diagnosis and monitoring of gliomas
Authors: Muralidharan Koushik , Yekula Anudeep , Small Julia L. , Rosh Zachary S. , Kang Keiko M. , Wang Lan , Lau Spencer , Zhang Hui , Lee Hakho , Bettegowda Chetan , Chicoine Michael R. , Kalkanis Steven N. , Shankar Ganesh M. , Nahed Brian V. , Curry William T. , Jones Pamela S. , Cahill Daniel P. , Balaj Leonora , Carter Bob S.
Published: September 2020

Liquid biopsy offers a minimally invasive tool to diagnose and monitor the heterogeneous molecular landscape of tumors over time and therapy. Gliomas have been challenging to sample with blood-based liquid biopsy due to low levels of circulating tumor-derived nucleic acid, and prior efforts have shown specific point mutations in less than 5% of glioma patients. Detection of TERT promoter mutations (C228T, C250T) in cfDNA has been successful for some systemic cancers but has yet to be demonstrated in gliomas, despite the high prevalence of these mutations in glioma tissue (>60% of all tumors). Here, we developed a novel digital droplet PCR (ddPCR) assay, that incorporates features to improve sensitivity and allows for the simultaneous detection and longitudinal monitoring of two TERT promoter mutations (C228T and C250T) in cfDNA from the plasma of glioma patients. In baseline performance in tumor tissue, (n= 157 samples), the assay had perfect concordance with an independently performed clinical pathology laboratory assessment of TERT promoter mutations in the same tumor samples (95% CI 94%-100%). Extending to matched plasma samples, we detected TERT mutations in both discovery and blinded multi-institution validation cohorts with an overall sensitivity of 62.5% (95% CI 52%-73%) and a specificity of 90% (95% CI 80%-96%) compared to the gold standard tumor tissue-based detection of TERT mutations. Upon longitudinal monitoring in 5 patients, we report that peripheral TERT mutant allele frequency reflects the clinical course of the disease with levels decreasing after surgical intervention and therapy and increasing with tumor progression. Our results demonstrate the feasibility of detecting circulating cfDNA TERT promoter mutations in glioma patients with clinically relevant sensitivity and specificity using a novel, enhanced ddPCR approach. The functionality of this assay also suggests a new clinical role for plasma-based cfDNA analysis to complement tissue-based histopathologic and molecular characterization for diagnosis and spatiotemporal monitoring of brain tumors.
Multiplexed, Microscale, Microarray-based Serological Assay for Antibodies Against All Human-Relevant Coronaviruses
Authors: Dawson Erica D. , Kuck Laura R. , Blair Rebecca H. , Taylor Amber W. , Toth Evan , Knight Vijaya , Rowlen Kathy L.
Published: September 2020

Rapid, sensitive, and precise multiplexed assays for serological analysis during candidate COVID-19 vaccine development would streamline clinical trials. The VaxArray Coronavirus (CoV) SeroAssay quantifies IgG antibody binding to 9 pandemic, potentially pandemic, and endemic human CoV spike antigens in 2 hours with automated results analysis. IgG antibodies in serum bind to the CoV spike protein capture antigens printed in a microarray format and are labeled with a fluorescent anti-species IgG secondary label. The assay demonstrated excellent lower limits of quantification ranging from 0.3 – 2.0 ng/mL and linear dynamic ranges of 76 to 911-fold. Average precision of 11% CV and accuracy (% recovery) of 92.5% over all capture antigens were achieved over 216 replicates representing 3 days and 3 microarray lots. Clinical performance on 263 human serum samples (132 SARS-CoV-2 negatives and 131 positives based on donor-matched RT-PCR and/or date of collection) produced 98.5% PPA (sensitivity) and 100% NPA (specificity).
Effectiveness of smartphone-based Community Case Management on urgent referral, re-consultation and hospitalization of children under-5 in Malawi: Results of a cluster-randomized, stepped-wedge trial
Authors: Chirambo Griphin Baxter , Thompson Matthew , Hardy Victoria , Ide Nicole , Hwang Phillip H. , Dharmayat Kanika I. , Mastellos Nikolaos , Heavin Ciara , O’Connor Yvonne , Muula Adamson S. , Andersson Bo , O’Donoghue John , Carlsson Sven , Tran Tammy , Chen-ling Hsieh Jenny , Lee Hsin-yi , Fitzpatrick Annette , Wu Joseph Tsung Shu
Published: September 2020

Background

Integrated community case management (CCM) has led to reductions in child mortality in Malawi from illnesses such as malaria, pneumonia and diarrhoea. However, adherence to CCM guidelines is often poor, potentially leading to inappropriate clinical decisions and outcomes. We determined the impact of an electronic version of CCM (eCCM) application on referral, re-consultation and hospitalization rates of children presenting to village clinics in Malawi.

Methods

A stepped-wedge cluster-randomized trial compared paper-based CCM (control) with and without use of an eCCM app on smartphones from November 2016 to April 2017.A total of 102 village clinics from two districts in Northern Malawi were assigned to one of six clusters which were randomized to the sequencing of crossover from the control to the intervention phases, as well as the duration of exposure in each phase. Children ≥2 months to <5 years presenting with acute illness were enrolled consecutively by Health Surveillance Assistants (HSAs). The primary outcome of urgent referrals to higher-level facilities was evaluated using multi-level mixed effects models. A logistic regression model with random effect of cluster and fixed effect for each step was fitted. Adjustment for potential confounders included baseline factors, such as patient’s age, sex, and geographical location of village clinics. Calendar time was adjusted for in the analysis.

Results

A total of 6965 children were recruited, 3421 in the control and 3544 in the intervention phase. After adjusting for calendar time, children in the intervention phase were more likely to be urgently referred to a higher-level health facility compared with children in the control phase (OR 2.02, 95% CI 1.27-3.23; p<0.01). Overall, children in the intervention arm had lower odds of attending a repeat HSA consultation (OR 0.45, 95% CI 0.34-0.59; p<0.01) or hospital admission (OR 0.75, 95% CI 0.62-0.90; p<0.01), but after adjusting for time these differences were not significant (p>0.05).

Conclusions

Addition of eCCM decision support led to a greater proportion of children being referred to higher-level facilities, with no apparent increase in hospital admissions or repeat consultations in village clinics. Our findings provide support for the implementation of eCCM tools in Malawi and other Low and Middle Income Countries (LMIC), with a need for ongoing assessment of effectiveness and integration with national digital health strategies.

Trial registration

http://ClinicalTrials.gov; NCT02763345. Registered 3 May 2016
A Mental Health Paradox: Mental health was both a motivator and barrier to physical activity during the COVID-19 pandemic
Authors: Marashi Maryam , Nicholson Emma , Ogrodnik Michelle , Fenesi Barbara , Heisz Jennifer
Published: September 2020

The COVID-19 pandemic has impacted the mental health, physical activity, and sedentary behavior of citizens worldwide. Using an online survey with 1669 respondents, we sought to understand why and how by querying about perceived barriers and motivators to physical activity that changed because of the pandemic, and how those changes impacted mental health. Consistent with prior reports, our respondents were less physically active (aerobic activity, −11%,p<0.05; strength-based activity, −30%,p<0.01) and more sedentary (+11%,p<0.01) during the pandemic as compared to 6-months before. The pandemic also increased psychological stress (+22%,p<0.01) and brought on moderate symptoms of anxiety and depression. Respondents’ whose mental health deteriorated the most were also the ones who were least active (depressionr= −.21,p<0.01; anxietyr= −.12,p<0.01). The majority of respondents were unmotivated to exercise because they were too anxious (+8%,p<0.01), lacked social support (+6%,p=<0.01), or had limited access to equipment (+23%,p<0.01) or space (+41%,p<0.01). The respondents who were able to stay active reported feeling less motivated by physical health outcomes such as weight loss (−7%,p<0.01) or strength (−14%,p<0.01) and instead more motivated by mental health outcomes such as anxiety relief (+14%,p<0.01). Coupled with previous work demonstrating a direct relationship between mental health and physical activity, these results highlight the potential protective effect of physical activity on mental health and point to the need for psychological support to overcome perceived barriers so that people can continue to be physically active during stressful times like the pandemic.
Sex-dependent pathways in hepatocarcinogenesis triggered by deregulated cholesterol synthesis
Authors: Blagotinšek Cokan Kaja , Urlep Žiga , Lorbek Gregor , Matz-Soja Madlen , Skubic Cene , Perše Martina , Jeruc Jera , Juvan Peter , Režen Tadeja , Rozman Damjana
Published: September 2020

We uncover novel pathways of sex-dependent hepatocarcinogenesis due to chronic repression of cholesterol synthesis at the lanosterol 14α-demethylase (CYP51) step. The response to metabolic insult determined by global liver transcriptome, qPCR and sterol metabolite analysis, together with blood parameters, revealed molecular signatures that differ between females and males. The data deduced from the mouse model are highly relevant for humans. The dampened hepatic metabolism presents a hallmark of carcinogenesis, particularly in ageing females, with increased plasma cholesterol and HDL, and a substantial negative enrichment of transcription factors from lipid metabolism, such as NR1B1, LXRα, LRH1, and FXR. Importantly, the carcinogenic signalling pathways (ECM-receptor interaction and PI3K/Akt) are positively enriched, albeit with sex-dependent gene targets. The activated TGF-β, mTOR, Wnt, and estrogen signalling worsen the phenotype, with NFATC1/2 being central to the female phenotype. This collectively leads to activated cell death and diminished basal metabolism. In conclusion, our data underline sex as an important biological variable of hepatocarcinogenesis. We uncover novel cholesterol-dependent transcription factors and signalling pathways as cancer markers in the ageing females.

Significance

Chronic repression of the late part of cholesterol synthesis provokes hepatocarcinogenesis with sex-dependent modulation of signalling pathways and transcription factors. Aging females show specific metabolic signatures and a more aggrevated phenotype of metabolism-related HCC.
Soluble RANKL exaggerates hindlimb suspension-induced osteopenia but not muscle protein balance
Authors: Speacht Toni L. , Lang Charles H. , Donahue Henry J.
Published: September 2020

We examined the hypothesis that exaggerating unloading-induced bone loss using a combination of hindlimb suspension (HLS) and exogenous injections of receptor activator of nuclear factor kappa-B ligand (RANKL) also exaggerates muscle loss. Forty, male C57Bl/6J mice (16 weeks) were subjected to HLS or normal ambulation (ground control, GC) for 14 days. Mice received 3 intraperitoneal injections of either human recombinant soluble RANKL or PBS as control (n=10/group) at 24 hour intervals starting on Day 1 of HLS. GC + RANKL and HLS mice exhibited similar decreases in trabecular bone volume and density in both proximal tibias and distal femurs. However, RANKL affected trabecular number, separation, and connectivity density, while HLS decreased trabecular thickness. The combination of RANKL and HLS exacerbated these changes. Similarly, GC + RANKL and HLS mice saw comparable decreases in cortical bone volume, thickness, and strength in femur midshafts, and combination treatment exacerbated these changes. Plasma concentrations of P1NP were increased in both groups receiving RANKL, while CTX concentrations were unchanged. HLS decreased gastrocnemius weight and was associated with a reduction in global protein synthesis, and no change in proteasome activity. This change was correlated with a decrease in S6K1 and S6 phosphorylation, but no change in 4E-BP1 phosphorylation. Injection of RANKL did not alter muscle protein metabolism in GC or HLS mice. Our results suggest that injection of soluble RANKL exacerbates unloading-induced bone loss, but not unloading-induced muscle loss. This implies a temporal disconnect between muscle and bone loss in response to unloading.
Epithelial and neutrophil interactions and coordinated response toShigellain a human intestinal enteroid-neutrophil co-culture model
Authors: Lemme-Dumit Jose M. , Doucet Michele , Zachos Nicholas C. , Pasetti Marcela F.
Published: September 2020

Polymorphonuclear neutrophils (PMN) are recruited to the gastrointestinal mucosa in response to inflammation, injury, and infection. Herein, we report the development and the characterization of anex vivotissue co-culture model consisting of human primary intestinal enteroid monolayers and PMN, and a mechanistic interrogation of PMN-epithelial cell interaction and response toShigella, a primary cause of childhood dysentery. Cellular adaptation and tissue integration, barrier function, PMN phenotypic and functional attributes, and innate immune responses were examined. PMN within the enteroid monolayers acquired a distinct activated/migratory phenotype that was influenced by direct epithelial cell contact as well as by molecular signals. Seeded on the basal side of the intestinal monolayer, PMN intercalated within the epithelial cells and moved paracellularly toward the apical side. Co-cultured PMN also increased basal secretion of IL-8.Shigellaadded to the apical surface of the monolayers evoked additional PMN phenotypic adaptations, including increased expression of cell surface markers associated with chemotaxis and cell degranulation (CD47, CD66b, and CD88). ApicalShigellainfection triggered rapid transmigration of PMN to the luminal side, NET formation as well as bacterial phagocytosis and killing.Shigellainfection modulated cytokine production in the co-culture; apical MCP-1, TNF-α, and basolateral IL-8 production were downregulated, while basolateral IL-6 secretion was increased. We demonstrated, for the first time, PMN phenotypic adaptation, mobilization, and coordinated epithelial cell-PMN innate response uponShigellainfection in the human intestinal environment. The enteroid monolayer-PMN co-culture represents a technical innovation for mechanistic interrogation of gastrointestinal physiology, host-microbe interaction, innate immunity, and evaluation of preventive/therapeutic tools.

Importance

Studies of mucosal immunity and microbial host cell interaction have traditionally relied on animal models andin vitrotissue culture using immortalized cancer cell lines, which render non-physiological and often unreliable results. Herein we report the development and characterization of anex vivoenteroid-PMN co-culture consisting of normal human intestinal epithelium and a mechanistic interrogation of PMN and epithelial cell interaction and function in the context ofShigellainfection. We demonstrated tissue-driven phenotypic and functional adaptation of PMN and a coordinated epithelial cell and PMN response toShigella, a primary cause of dysentery in young children in the developing world.
A multi-scale pipeline linking drug transcriptomics with pharmacokinetics predictsin vivointeractions of tuberculosis drugs
Authors: Cicchese Joseph , Sambarey Awanti , Kirschner Denise , Linderman Jennifer , Chandrasekaran Sriram
Published: September 2020

Tuberculosis (TB) is the deadliest infectious disease worldwide. The design of new treatments for TB is hindered by the large number of candidate drugs, drug combinations, dosing choices, and complex pharmaco-kinetics/dynamics (PK/PD). Here we study the interplay of these factors in designing combination therapies by linking a machine-learning model, INDIGO-MTB, which predictsin vitrodrug interactions using drug transcriptomics, with a multi-scale model of drug PK/PD and pathogen-immune interactions calledGranSim. We calculate anin vivodrug interaction score (iDIS) from dynamics of drug diffusion, spatial distribution, and activity within lesions against various pathogen sub-populations. The iDIS of drug regimens evaluated against non-replicating bacteria significantly correlates with efficacy metrics from clinical trials. Our approach identifies mechanisms that can amplify synergistic or mitigate antagonistic drug interactionsin vivoby modulating the relative distribution of drugs. Our mechanistic framework enables efficient evaluation ofin vivodrug interactions and optimization of combination therapies.
Boosting the analysis of protein interfaces with Multiple Interface String Alignment:illustration on the spikes of coronaviruses
Authors: Bereux S. , Delmas B. , Cazals F.
Published: September 2020

We introduceMultiple Interface String Alignment(MISA), a visualization tool to display coherently various sequence and structure based statistics at protein-protein interfaces (SSE elements, buried surface area, ΔASA, B factor values, etc). The amino-acids supporting these annotations are obtained from Voronoi interface models. The benefit of MISA is to collate annotated sequences of (homologous) chains found in different biological contextsi.e.bound with different partners or unbound. The aggregated views MISA/SSE, MISA/BSA, MISA/Δ ASAetc make it trivial to identify commonalities and differences between chains, to infer key interface residues, and to understand where conformational changes occur upon binding. As such, they should prove of key relevance for knowledge based annotations of protein databases such as the Protein Data Bank.

Illustrations are provided on the receptor binding domain (RBD) of coronaviruses, in complex with their cognate partner or (neutralizing) antibodies. MISA computed with a minimal number of structures complement and enrich findings previously reported.

The corresponding package is available from the Structural Bioinformatics Library (http://sbl.inria.fr)
Integrating GPU support for FreeSurfer with OpenACC
Authors: Shen Jingcheng , Mei Jie , Walldén Marcus , Ino Fumihiko
Published: September 2020

FreeSurfer is among the most widely used suites of software for the study of cortical and subcortical brain anatomy. However, analysis using FreeSurfer can be time-consuming and it lacks support for the graphics processing units (GPUs) after the core development team stopped maintaining GPU-accelerated versions due to significant programming cost. As FreeSurfer is a large project with millions of source lines, in this work, we introduce and examine the use of a directive-based framework, OpenACC, in GPU acceleration of FreeSurfer, and we found the OpenACC-based approach significantly reduces programming costs. Moreover, because the overhead incurred by CPU-to-GPU data transfer is the major challenge in delivering GPU-based codes of high performance, we compare two schemes, copy- and-transfer and overlapped-fully-transfer, to reduce such data transfer overhead. Exper-imental results show that the target function we accelerated with overlapped-fully-transfer scheme ran 2.3 as fast as the original CPU-based function, and the GPU-accelerated program achieved an average speedup of 1.2 compared to the original CPU-based program. These results demonstrate the usefulness and potential of utilizing the proposed OpenACC-based approach to integrate GPU support for FreeSurfer which can be easily extended to other computationally expensive functions and modules of FreeSurfer to achieve further speedup.
Quantitative analysis of transporter activity biosensors
Authors: Park Jihyun , Chavez Taylor M. , Frommer Wolf B. , Cheung Lily S.
Published: September 2020

The allocation of sugars from photosynthetic leaves to storage tissues in seeds, fruits, and tubers is an important determinant of crop yields. Genetically guided selection and transgenic modification of plant membrane transporters can help enhance crop yields and increase pathogen resistance. Yet, quantitative, systems-level models to support this effort are lacking. Recently, biosensors gained popularity for collecting spatiotemporally resolved information on cell physiology and validating computational models. Here, we report the design and use of genetically-encoded biosensors to measure the activity of SWEETs, the only family of sugar transporters known to facilitate the cellular release of sugar in plants. We created SweetTrac sensors by inserting circularly-permutated GFP into SWEET transporters, resulting in chimeras that translate substrate-triggered conformational rearrangements during the transport cycle into detectable changes in fluorescence intensity. We demonstrate that a combination of cell sorting and bioinformatics can be applied as a general approach to accelerate the design of biosensors forin vivobiochemistry. Finally, mass action kinetics analysis of the biosensors’ response suggests that SWEETs are low-affinity, near-symmetric transporters that can rapidly equilibrate intra- and extracellular concentrations of sugars.

Significance Statement

Transporters are the gatekeepers of the cell. Transporters facilitate the exchange of ions and metabolites between cellular and subcellular compartments, thus controlling processes from bacterial chemotaxis to the release of neurotransmitters. In plants, transporters play critical roles in the allocation of carbon to different organs. Biosensors derived from transporters have been generated to monitor the activity of these proteins within the complex environment of the cell. However, a quantitative framework that reconciles molecular and cellular-level events to help interpret the response of biosensors is still lacking. Here, we created novel sugar transport biosensors and formulated a mathematical model to explain their response. These types of models can help realize multiscale, dynamic simulations of metabolite allocation to guide crop improvement.
A Novel Role for the Nuclear Receptor, NR4A1, inKlebsiella pneumoniaeLung Infection
Authors: Partyka Jessica , Henkel Matthew , Campfield Brian T.
Published: September 2020

Klebsiella pneumoniaeis a Gram-negative bacterial pathogen and common cause of pneumonia and bacteremia. Increasingly,K. pneumoniaehas become a public health concern due to its rate of nosocomial infection and emerging, broad-spectrum antibiotic resistance. The nuclear receptor NR4A1 exhibits functionality in a multitude of organ systems and is implicated as having a role in the immune response to bacterial infection, though its role inK. pneumoniaeinfection is unknown. To determine ifNr4a1functions in response toK. pneumoniaepulmonary disease, we infected wild-type andNr4a1−/−mice withK. pneumoniaeand assessed bacterial growth, immune cell recruitment and function, and cytokine production. We found thatNr4a1−/−mice had increased bacterial burden in the lungs and spleen, though no differences in cell recruitment. Pro-inflammatory cytokines,Il1βandIl6, as well as chemokine,Cxcl2, were significantly decreased in the BAL fluid cells ofNr4a1−/−mice 5 hours post-infection. Additionally,Nr4a1−/−mice had reduced IL-1β and myeloperoxidase protein production. We then examined the bactericidal function of macrophages and neutrophils from WT andNr4a1−/−mice. We identified thatNr4a1−/−neutrophils had decreased bactericidal function compared to wild-type neutrophils, which was associated with reduced expression ofIl1β,Lcn2,Mpo, andLyz2. These data suggestNr4a1plays a novel and essential role in neutrophil function during the host immune response toK. pneumoniaepulmonary infection.
Representative bubbles and deleveraging
Authors: Strati Francesco
Published: September 2020

Purpose

The causes for the formation of a bubble in the collateral market when agents are provided with homogeneous expectations are explored. This bubbly dynamics will define a sufficient condition for deleveraging.

Design/methodology/approach

Theoretical approach with neutral deleveraging.

Findings

Findings of the study are defined sufficient conditions for a behavioral rational bubble's formation in a market of collateral and the subsequent deleveraging. The crowd-in effect of the representative bubble is caused by errors in extrapolating information and thus by representativeness, while the crowd-out effect of deleveraging is set off by reverting to a rational heuristic.

Research limitations/implications

The limit is that it is a homogeneous expectations approach, the implication is that cannot be rational speculation.

Practical implications

Even in a simple model of homogeneous expectations a bubble may arise with serious effect on the demand side: models that detect just rational mispricings cannot account for behavioral components that have financial and real effects.

Originality/value

The paper defines how deleveraging may occur even in case of homogeneous expectations. The latter should not be seen just as a limit but also as a signal of the importance of being aware of behavioral components.
Growth of private university business following “oligopoly” and “SME” approaches: an impact on the concept of university and on society
Authors: Alam Gazi Mahabubul , Parvin Morsheda , Roslan Samsilah
Published: September 2020

Purpose

Universally, university is considered as the apex body which is ethically obliged to present a substantial society. In doing so, universities often innovate dynamic business models and theories. Ideally, the countries whose universities contribute for better and sustainable business growth are the advanced one. However, universities themselves should be the business organisation – an argument is yet to receive attention. Although literature lacks in the area of education business especially university provision, the sector behaves as business entity after the inception of private sector. Therefore, this paper aims to explore the paradigm transformation of university sector and its impact on the society.

Design/methodology/approach

Given the differentiated nature of research questions, multiple techniques are used to collect the data. However, this research adopts the norms of qualitative methods. Both secondary and primary data are used. While secondary data are collected by University Grants Commission (UGC), primary data are collected through interviews.

Findings

Findings show that the development of university sector started following monopoly model. More than half a century, the same model was continued. Thereafter, duopoly model was introduced which carried until the inception of private sector. The growth of private sector followed oligopoly model which was further extended to small and medium enterprises (SMEs). These days, society compares university with “diploma mill”, as production of knowledge and civic society is longer than the part of the core business of university. Consequently, compromising with research is to be judged as a threat to overall development that includes business and social development.

Originality/value

A few studies have been published in the area of private university. To the best of the authors’ knowledge, none covers the oligopoly-ism and SME-ism behaviour of university and its impact on the concept of university and on the society. Therefore, this project aims to understand the norms of university business and its substantial contribution on the social change.