bluuebunny/crossref_metadata_2025 huggingface dataset:
Time to definitive fixation of pelvic and acetabular fractures
Authors: Devaney Giles L. , Bulman James , King Kate L. , Balogh Zsolt J.
Published: July 2020

BACKGROUND

The timing of definitive surgical stabilization is a controversial topic of pelvic and acetabular fracture (PAF) management. Historically, staged care with delayed definitive fixation was recommended; however, more recently, some centers have shown early definitive fixation to be feasible in most patients. We hypothesized that time to definitive fixation of PAF decreased without adverse outcomes.

METHODS

A level 1 trauma center's prospective pelvic fracture database was retrospectively analyzed. A total of 341 of the 1,270 consecutive PAF patients had surgery between January 2009 and December 2018. Demographics, polytrauma status, hemodynamic stability, time to definitive operation, length of intensive care unit stay, hospital length of stay, mortality were recorded. Data is presented as mean ± SD, percentages. Statistical significance was determined at p < 0.05.

RESULTS

There were 34 ± 8 per year operatively treated PAF patients during the study period. The demographics (age, 44.1 ± 18 years; 74.5% males) and injury severity (Injury Severity Score, 20; interquartile range, 16–29) did not change. Time to definitive fixation on average was 85 ± 113 hours (range, 0.8–1286 hours). Linear regression analysis demonstrated a decrease in time to definitive fixation considering all patients (β = −0.186, p = 0.003). pelvic ring fractures with polytrauma (β = −1.404, p = 0.03). and hemodynamically unstable patients (β = −1.428, p = 0.037). There was no significant change in mortality, length of stay, or intensive care unit length of stay for the overall cohort or any subgroup.

CONCLUSION

Time to definitive fixation in PAF has decreased during the last decade, with the largest decrease in time to fixation occurring in the hemodynamically unstable and pelvic fracture with polytrauma cohorts. The timely definitive internal fixation is achievable without increased length of stay.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
The neuroprotective effect of quetiapine in critically ill traumatic brain injury patients
Authors: Asmar Samer , Lokhandwala Adil , Richards Joseph , Bible Letitia , Avila Mauricio , Castanon Lourdes , Ditillo Michael , Douglas Molly , Joseph Bellal
Published: July 2020

INTRODUCTION

Quetiapine is an atypical antipsychotic commonly used in critical care. Cellular and animal models demonstrated its novel anti-inflammatory properties in traumatic brain injury (TBI). Our study aimed to assess the effect of quetiapine on outcomes in critically ill TBI patients. We hypothesize that quetiapine improves neurological outcomes.

METHODS

The Multiparameter Intelligent Monitoring in Intensive Care database was queried, and all adult (age, ≥18 years) isolated TBI patients (extracranial Abbreviated Injury Scale, < 2) admitted to the intensive care unit for a period of >48 hours. Patients were stratified into quetiapine (+) and no-quetiapine (−) groups. Propensity score matching was performed (1:2 ratio). Outcome measures were intensive care unit length of stay, discharge Glasgow Coma Scale (GCS), and mortality. A subanalysis was performed for patients who underwent intracranial pressure (ICP) monitoring to ascertain the effect of quetiapine dose on ICP, and cerebral perfusion pressure (CPP). Survival curves and regression analyses were performed.

RESULTS

A matched cohort of (quetiapine, 116 vs. no-quetiapine, 232) patients was obtained. Mean ± SD age was 65 ± 21 years, median head Abbreviated Injury Scale was 3 (3–4), and median GCS was 10 (9–16). The median quetiapine dose given was 50 (25–125) mg. Patients who received quetiapine had lower mortality (17.2% vs. 27.6%; p = 0.03) and a higher median GCS at discharge (12 [11–14] vs. 11 [10–13]; p < 0.04) but no difference in intensive care unit length of stay (4.1 days vs. 4.7 days; p = 0.75) or discharge to skilled nursing facility (34.5% vs. 31.9%; p = 0.63). On subanalysis of patients who received quetiapine, 40% had ICP monitoring. Higher doses of quetiapine were independently associated with progressively lower ICP (β = −0.022 mm Hg/mg of quetiapine; p = 0.01) and higher CPP (β = 0.031 mm Hg/mg quetiapine; p = 0.01).

CONCLUSION

Quetiapine may decrease mortality and improve neurological outcomes in critically ill TBI patients. It has a dose-dependent effect to decrease ICP and increase CPP. Quetiapine may be a potential therapeutic modality in critically ill TBI patients, but further studies are required to explore these mechanisms.

LEVEL OF EVIDENCE

Systematic Review, level III.
Nationwide analysis of resuscitative thoracotomy in pediatric trauma: Time to differentiate from adult guidelines?
Authors: Prieto James M. , Van Gent Jan Michael , Calvo Richard Y. , Rooney Alexandra S. , Martin Matthew J. , Sise Michael J. , Sise C. Beth , Lazar David A. , Bansal Vishal , Ignacio Romeo C.
Published: July 2020

BACKGROUND

Emergency department thoracotomy (EDT) for pediatric patients is uncommon, and practice patterns have not been evaluated. We examined the indications and outcomes for EDT by trauma center designation using a nationwide database.

METHODS

Patients 16 years or younger who underwent EDT within 30 minutes of arrival from 2013 to 2016 were identified in the American College of Surgeons National Trauma Data Bank. Patient demographic information, indications for EDT, and outcomes were analyzed. Outcomes were compared between centers with and without pediatric trauma center designation.

RESULTS

A total of 114 patients were identified for analysis with a mean ± SD age of 10.3 ± 4.7 years. Patients were predominantly male (69%) with a median Injury Severity Score of 26 (interquartile range, 18–42). Penetrating trauma occurred in 56%. Overall, mortality was 90% and was similar in penetrating and blunt trauma (88% vs. 94%; p = 0.34). There were no survivors among the 53 patients (46%) who arrived with no signs of life. Among the 11 patients (10%) who survived, median length of stay was 26 days (interquartile range, 6–28 days). Overall, 8% of EDT was performed at free-standing pediatric trauma centers, 45% at adult centers, and 47% at combined trauma centers. Mortality rates and indications were similar among trauma centers regardless of designation status.

CONCLUSION

In a national population-based data set, the mortality after pediatric EDT is high, and many of these procedures are performed at nonpediatric trauma centers. Regardless of injury mechanism, EDT is not appropriate in children without signs of life on arrival. Pediatric guidelines are needed to increase awareness of the poor outcomes and limited indications for EDT.

LEVEL OF EVIDENCE

Therapeutic, level IV.
Comparison of postoperative complications between open and laparoscopic appendectomy: An umbrella review of systematic reviews and meta-analyses
Authors: Poprom Napaphat , Wilasrusmee Chumpon , Attia John , McEvoy Mark , Thakkinstian Ammarin , Rattanasiri Sasivimol
Published: July 2020

BACKGROUND

Laparoscopic appendectomy (LA) has been popular for decades because of shorter hospitalization and return to routine activity. However, complications (e.g., surgical site infection [SSI] and intra-abdominal abscess [IAA]) relative to open appendectomy (OA) are still debated. We therefore conducted an umbrella review to systematically appraise meta-analyses (MAs) comparing SSI and IAA between LA and OA.

METHODS

Meta-analyses that included only randomized controlled trials were identified from MEDLINE and Scopus databases from inception until July 2018. Their findings were described, the number of overlapping studies was assessed using corrected covered area, and excess significant tests were also assessed. Finally, effect sizes of SSI and IAA were repooled.

RESULTS

Ten MAs were eligible; SSI was reported in all MAs and IAA in 8 MAs. Surgical site infection rate was 48% to 70% lower in LA than OA, but conversely, IAA rate was 1.34 to 2.20 higher in LA than OA. Overlapping included studies for SSI and IAA were 61% and 54%, respectively, indicating that less information was added across MAs. However, there was no evidence of bias from excess significant tests when pooling SSI or IAA estimates. The risk ratios (95% confidence interval) comparing LA versus OA were repooled in adults and children yielding risk ratios of 0.56 (0.47–0.67) and 0.40 (0.25–0.65) for SSI, and 1.20 (0.88–1.63) and 1.05 (0.61–1.80) for IAA.

CONCLUSION

Evidence from this umbrella review indicates that LA carries a significantly lower risk of SSI but likely a higher risk of IAA than OA.

LEVEL OF EVIDENCE

Systematic review/meta-analysis, level I.
Novel regulators of the csgD gene encoding the master regulator of biofilm formation in Escherichia coli K-12
Authors: Ogasawara Hiroshi , Ishizuka Toshiyuki , Hotta Shuhei , Aoki Michiko , Shimada Tomohiro , Ishihama Akira
Published: July 2020

Under stressful conditions,

Escherichia coli

forms biofilm for survival by sensing a variety of environmental conditions. CsgD, the master regulator of biofilm formation, controls cell aggregation by directly regulating the synthesis of Curli fimbriae. In agreement of its regulatory role, as many as 14 transcription factors (TFs) have so far been identified to participate in regulation of the csgD promoter, each monitoring a specific environmental condition or factor. In order to identify the whole set of TFs involved in this typical multi-factor promoter, we performed in this study ‘promoter-specific transcription-factor’ (PS-TF) screening in vitro using a set of 198 purified TFs (145 TFs with known functions and 53 hitherto uncharacterized TFs). A total of 48 TFs with strong binding to the csgD promoter probe were identified, including 35 known TFs and 13 uncharacterized TFs, referred to as Y-TFs. As an attempt to search for novel regulators, in this study we first analysed a total of seven Y-TFs, including YbiH, YdcI, YhjC, YiaJ, YiaU, YjgJ and YjiR. After analysis of curli fimbriae formation, LacZ-reporter assay, Northern-blot analysis and biofilm formation assay, we identified at least two novel regulators, repressor YiaJ (renamed PlaR) and activator YhjC (renamed RcdB), of the csgD promoter.
Structural transitions in Orb2 prion-like domain relevant for functional aggregation in memory consolidation
Authors: Oroz Javier , Félix Sara S. , Cabrita Eurico J. , Laurents Douglas V.
Published: July 2020

The recent structural elucidation ofex vivo DrosophilaOrb2 fibrils revealed a novel amyloid formed by interdigitated Gln and His residue side chains belonging to the prion-like domain. However, atomic-level details on the conformational transitions associated with memory consolidation remain unknown. Here, we have characterized the nascent conformation and dynamics of the prion-like domain (PLD) of Orb2A using a nonconventional liquid-state NMR spectroscopy strategy based on13C detection to afford an essentially complete set of13Cα,13Cβ,1Hα and backbone13CO and15N assignments. At pH 4, where His residues are protonated, the PLD is disordered and flexible, except for a partially populated α-helix spanning residues 55-60. At pH 7, in contrast, His residues are predominantly neutral and the Q/H segments adopt minor populations of helical structure, show decreased mobility and start to self-associate. At pH 7, the His residues also bind Zn++, which promotes further association. These findings represent a remarkable case of structural plasticity, based on which an updated model for Orb2A functional amyloidogenesis is advanced.

Highlights

· The Orb2 prion like domain that forms the structures related to memory consolidation is studied by solution NMR.

· The amyloidogenic Q/H-rich stretch is disordered and flexible at low pH.

· Residues 55-60 form a partly populated α-helix at pH 4.

· At pH 7, the Q/H-rich segment also adopts a low population of α-helix and rigidifies.

· Zn++binding induces associative changes in the Orb2 prion-like domain.
Bootstrap aggregating improves the generalizability of Connectome Predictive Modelling
Authors: O’Connor David , Lake Evelyn M.R. , Scheinost Dustin , Constable R. Todd
Published: July 2020

It is a long-standing goal of neuroimaging to produce reliable generalized models of brain behavior relationships. More recently data driven predicative models have become popular. Overfitting is a common problem with statistical models, which impedes model generalization. Cross validation (CV) is often used to give more balanced estimates of performance. However, CV does not provide guidance on how best to apply the models generated out-of-sample. As a solution, this study proposes an ensemble learning method, in this case bootstrap aggregating, or bagging, encompassing both model parameter estimation and feature selection. Here we investigate the use of bagging when generating predictive models of fluid intelligence (fIQ) using functional connectivity (FC). We take advantage of two large openly available datasets, the Human Connectome Project (HCP), and the Philadelphia Neurodevelopmental Cohort (PNC). We generate bagged and non-bagged models of fIQ in the HCP. Over various test-train splits, these models are evaluated in sample, on left out HCP data, and out-of-sample, on PNC data. We find that in sample, a non-bagged model performs best, however out-of-sample the bagged models perform best. We also find that feature selection can vary substantially within-sample. A more considered approach to feature selection, alongside data driven predictive modeling, is needed to improve cross sample performance of FC based brain behavior models.
CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response
Authors: Biasci Daniele , Smoragiewicz Martin , Connell Claire M. , Wang Zhikai , Gao Ya , Thaventhiran James , Basu Bristi , Magiera Lukasz , Johnson Isaac T. , Bax Lisa , Gopinathan Aarthi , Isherwood Christopher , Gallagher Ferdia , Pawula Maria , Hudecova Irena , Gale Davina , Rosenfeld Nitzan , Barmpounakis Petros , Popa Elizabeta Cristina , Brais Rebecca , Godfrey Edmund , Mir Fraz , Richards Frances , Fearon Douglas T. , Janowitz Tobias , Jodrell Duncan
Published: July 2020

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anti-cancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition effects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all the immune cell types that participate in an integrated immune responses. Inhibiting CXCR4 in an experimental cancer medicine study by one-week continuous infusion of the small molecule inhibitor, AMD3100 (plerixafor), induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to non-infected tissues: rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human PDA and CRC by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.

Statement of significance

Continuous infusion of AMD3100, an antagonist of the chemokine receptor, CXCR4, induces an integrated anti-cancer immune response in metastases of patients with microsatellite stable pancreatic and colorectal cancer that is predictive of response to T cell checkpoint inhibition.
The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19
Authors: Consiglio Camila Rosat , Cotugno Nicola , Sardh Fabian , Pou Christian , Amodio Donato , Rodriguez Lucie , Tan Ziyang , Zicari Sonia , Ruggiero Alessandra , Pascucci Giuseppe Rubens , Santilli Veronica , Campbell Tessa , Bryceson Yenan , Eriksson Daniel , Wang Jun , Marchesi Alessandra , Lakshmikanth Tadepally , Campana Andrea , Villani Alberto , Rossi Paolo ,   the CACTUS study team, Landegren Nils , Palma Paolo , Brodin Petter
Published: July 2020

SARS-CoV-2 infection is typically very mild and often asymptomatic in children. A complication is the rare Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19, presenting 4-6 weeks after infection as high fever, organ dysfunction and strongly elevated markers of inflammation. The pathogenesis is unclear but has overlapping features with Kawasaki disease suggestive of vasculitis and a likely autoimmune etiology. We apply systems-level analyses of blood immune cells, cytokines and autoantibodies in healthy children, children with Kawasaki disease enrolled prior to COVID-19, children infected with SARS-CoV-2 and children presenting with MIS-C. We find that the inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T-cell subsets, IL-17A and biomarkers associated with arterial damage. Finally, autoantibody profiling suggests multiple autoantibodies that could be involved in the pathogenesis of MIS-C.

HIGHLIGHTS

Hyperinflammation in MIS-C differs from that of acute COVID-19

T-cell subsets discriminate Kawasaki disease patients from MIS-C

IL-17A drives Kawasaki, but not MIS-C hyperinflammation.

Global autoantibodies profiling indicate possibly pathogenic autoantibodies
Comorbidity of self-harm and disordered eating in young people: Evidence from a UK population-based cohort
Authors: Warne Naomi , Heron Jon , Mars Becky , Moran Paul , Stewart Anne , Munafò Marcus , Biddle Lucy , Skinner Andy , Gunnell David , Bould Helen
Published: July 2020

Self-harm and eating disorders are often comorbid in clinical samples but their co-occurrence in the general population is unclear. We assessed the co-occurrence of self-harm and disordered eating behaviours at age 16 and 24 years in 3384 females and 2326 males from a UK population-based cohort. There was substantial overlap at both time points: almost two-thirds of 16-year-old females, and two-in-five 24-year old males who self-harmed also reported disordered eating. Among young people, self-harm may signal the occurrence of disordered eating and vice versa. It is important to screen for both sets of difficulties to provide appropriate treatment.
Determinants of disease prevalence and antibiotic consumption for children under five in Nepal: analysis and modelling of Demographic Health Survey data from 2006 to 2016
Authors: Zheng Charlotte , Karkey Abilasha , Wang Tianyi , van Doorn H. Rogier , Lewycka Sonia
Published: July 2020

Objectives

Our aims were to examine the geographic, socio-economic and behavioural factors associated with disease and antibiotic consumption in Nepal between 2006 and 2016 and to explore healthcare seeking patterns and the source of antibiotics.

Methods

Cross-sectional data from children under five in households in Nepal was extracted from the 2006, 2011 and 2016 Demographic Health Surveys (DHS). Univariate and multivariate analyses were carried out to assess the association of disease prevalence and antibiotic use with age, sex, ecological zone, urban/rural location, wealth index, maternal smoking, use of clean fuel, sanitation, nutrition, access to healthcare and vaccinations.

Results

Prevalence of fever, acute respiratory infection (ARI) and diarrhoea decreased between 2006 and 2016, while the proportion using antibiotics increased. Wealth, use of clean fuel, improved toilet sanitation, nutrition and access to healthcare were associated with reduced rates of disease. Those in the highest wealth index use less antibiotics and antibiotic consumption in rural areas surpassed urban regions over time. Health-seeking from the private sector has overtaken government facilities since 2006 with antibiotics mainly originating from pharmacies and private hospitals. Adherence to WHO recommended antibiotics has reduced over time.

Conclusions

With rising wealth, there has been a decline in disease prevalence but an increase in antibiotic use with more access to unregulated sources. Understanding antibiotic use and identifying associated behavioural and socio-economic factors may help to inform interventions to reduce inappropriate antibiotic use whilst ensuring access to those who need them.
The molecular architecture of CenH3-deficient holocentromeres in Lepidoptera is dependent on transcriptional and chromatin dynamics
Authors: Senaratne Aruni P. , Muller Héloïse , Fryer Kelsey A. , Drinnenberg Ines A.
Published: July 2020

Despite their essentiality for chromosome segregation, centromeres are diverse among eukaryotes and embody two main configurations: mono- and holocentromeres, referring respectively to a localized or unrestricted distribution of centromeric activity. Previous studies revealed that holocentricity in many insects coincides with the loss of the otherwise essential centromere component CenH3 (CENP-A), suggesting a molecular link between the two events. In this study, we leveraged recently-identified centromere components to map and characterize the centromeres of Bombyx mori. This uncovered a robust correlation between centromere profiles and regions of low chromatin dynamics. Transcriptional perturbation experiments showed that low chromatin activity is crucial for centromere formation inB. mori. Our study points to a novel mechanism of centromere formation that occurs in a manner recessive to the chromosome-wide chromatin landscape. Based on similar profiles in additional Lepidoptera, we propose an evolutionarily conserved mechanism that underlies the establishment of holocentromeres through loss of centromere specificity.
Air and surface contamination in non-health care settings among 641 environmental specimens of 39 COVID-19 cases
Authors: Luo Lei , Liu Dan , Zhang Hao , Li Zhihao , Zhen Ruonan , Zhang Xiru , Xie Huaping , Song Weiqi , Liu Jie , Huang Qingmei , Liu Jingwen , Yang Xingfen , Chen Zongqiu , Mao Chen
Published: July 2020

Background

Little is known about the SARS-CoV-2 contamination of environmental surfaces and air in non-health care settings among COVID-19 cases.

Methods and findings

We explored the SARS-CoV-2 contamination of environmental surfaces and air by collecting air and swabbing environmental surfaces among 39 COVID-19 cases in Guangzhou, China. The specimens were tested by RT-PCR testing. The information collected for COVID-19 cases included basic demographic, clinical severity, onset of symptoms, radiological testing, laboratory testing and hospital admission. A total of 641 environmental surfaces and air specimens were collected among 39 COVID-19 cases before disinfection. Among them, 20 specimens (20/641, 3.1%) were tested positive from 9 COVID-19 cases (9/39, 23.1%), with 5 (5/101, 5.0%) positive specimens from 3 asymptomatic cases, 5 (5/220, 2.3%) from 3 mild cases, and 10 (10/374, 2.7%) from 3 moderate cases. All positive specimens were collected within 3 days after diagnosis, and 10 (10/42, 23.8%) were found in toilet (5 on toilet bowl, 4 on sink/faucet/shower, 1 on floor drain), 4 (4/21, 19.0%) in anteroom (2 on water dispenser/cup/bottle, 1 on chair/table, 1 on TV remote), 1 (1/8, 12.5%) in kitchen (1 on dining-table), 1 (1/18, 5.6%) in bedroom (1 on bed/sheet pillow/bedside table), 1 (1/5, 20.0%) in car (1 on steering wheel/seat/handlebar) and 3 (3/20, 21.4%) on door knobs. Air specimens in room (0/10, 0.0%) and car (0/1, 0.0%) were all negative.

Conclusions

SARS-CoV-2 was found on environmental surfaces especially in toilet, and could survive for several days. We provided evidence of potential for SARS-CoV-2 transmission through contamination of environmental surfaces.
A single cell atlas of human cornea that defines its development, limbal stem and progenitor cells and the interactions with the limbal niche
Authors: Collin Joseph , Queen Rachel , Zerti Darin , Bojic Sanja , Moyse Nicky , Molina Marina Moya , Yang Chunbo , Reynolds Gary , Hussain Rafiqul , Coxhead Jonathan M , Lisgo Steven , Henderson Deborah , Joseph Agatha , Rooney Paul , Ghosh Saurabh , Connon Che , Haniffa Muzlifah , Figueiredo Francisco , Armstrong Lyle , Lako Majlinda
Published: July 2020

To study the development and composition of human ocular surface, we performed single cell (sc) RNA-Seq at key embryonic, fetal and adult stages and generated the first atlas of the corneal cell types from development to adulthood. Our data indicate that during development, the conjunctival epithelium is the first to be specified from the ocular surface epithelium, followed by the corneal epithelium and the establishment of proliferative epithelial progenitors, which predate the formation of limbal niche by a few weeks. Bioinformatic comparison of adult cell clusters identified GPHA2, a novel cell-surface marker for quiescent limbal stem cells (qLSCs), whose function is to maintain qLSCs self-renewal. Combining scRNA- and ATAC-Seq analysis, we identified multiple upstream regulators for qLSCs and transit amplifying (TA) cells and demonstrated a close interaction between the immune cells and epithelial stem and progenitor cells in the cornea. RNA-Seq analysis indicated loss of qLSCs and acquisition of proliferative limbal basal epithelial progenitor markers duringex vivolimbal epithelial cell expansion, independently of the culture method used. Extending the single cell analyses to keratoconus, we were able to reveal activation of collagenase in the corneal stroma and a reduced pool of TA cells in the limbal epithelium as two key changes underlying the disease phenotype. Our scRNA- and ATAC-Seq data of developing and adult cornea in steady state and disease conditions provide a unique resource for defining pathways/genes that can lead to improvement inex vivoexpansion and differentiation methods for cell based replacement therapies and better understanding and treatment of ocular surface disorders.

Key findings

scRNA-Seq of adult human cornea and conjunctiva reveals the signature of various ocular surface cell populations

scRNA-Seq of human developing cornea identifies stage-specific definitions of corneal epithelial, stromal and endothelial layers

scRNA-Seq analysis results in identification of novel markers for qLSCs and TA cells

Combined scRNA- and ATAC-Seq analysis reveals key transcriptional networks in qLSCs and TA cells and close interactions with immune cells

Expansion of limbal epithelium results in downregulation of qLSCs and acquisition of proliferative limbal epithelial progenitor markers

scRNA-Seq of keratoconus corneas reveals activation of collagenase in the corneal stroma and a reduced pool of TA cells in the limbal epithelium

Graphical abstract

Schematic presentation of main techniques and findings presented in this manuscript.
Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice
Authors: Snyder Jessica M , Zhong Guo , Hogarth Cathryn , Huang Weize , Topping Traci , LaFrance Jeffrey , Palau Laura , Czuba Lindsay C , Griswold Michael , Ghiaur Gabriel , Isoherranen Nina
Published: July 2020

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of theatRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increasesatRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the mainatRA clearing Cyp in post-natal mammals. This hypothesis was tested by generating tamoxifen inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T-lymphocytes into the skin and hyperkeratosis/hyperplasia of the non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.
Repeat SARS-CoV-2 Testing Models for Residential College Populations
Authors: Chang Joseph T. , Crawford Forrest W. , Kaplan Edward H.
Published: July 2020

Residential colleges are considering re-opening under uncertain futures regarding the COVID-19 pandemic. We consider repeat SARS-CoV-2 testing models for the purpose of containing outbreaks in the residential campus community. The goal of repeat testing is to detect and isolate new infections rapidly to block transmission that would otherwise occur both on and off campus. The models allow for specification of aspects including scheduled on-campus resident screening at a given frequency, test sensitivity that can depend on the time since infection, imported infections from off campus throughout the school term, and a lag from testing until student isolation due to laboratory turnaround and student relocation delay. For early- (late-) transmission of SARS-CoV-2 by age of infection, we find that weekly screening cannot reliably contain outbreaks with reproductive numbers above 1.4 (1.6) if more than one imported exposure per 10,000 students occurs daily. Screening every three days can contain outbreaks providing the reproductive number remains below 1.75 (2.3) if transmission happens earlier (later) with time from infection, but at the cost of increased false positive rates requiring more isolation quarters for students testing positive. Testing frequently while minimizing the delay from testing until isolation for those found positive are the most controllable levers for preventing large residential college outbreaks. Aweb appthat implements model calculations is available to facilitate exploration and consideration of a variety of scenarios.
Severe SAR-CoV-2 infection in humans is defined by a shift in the serum lipidome resulting in dysregulation of eicosanoid immune mediators
Authors: Schwarz Benjamin , Sharma Lokesh , Roberts Lydia , Peng Xiaohua , Bermejo Santos , Leighton Ian , Massana Arnau Casanovas , Farhadian Shelli , Ko Albert I. ,   Yale IMPACT Team, Dela Cruz Charles S. , Bosio Catharine M.
Published: July 2020

Introductory Paragraph

The COVID-19 pandemic has affected more than 10 million people worldwide with mortality exceeding half a million patients. Risk factors associated with severe disease and mortality include advanced age, hypertension, diabetes, and obesity.1 Clear mechanistic understanding of how these comorbidities converge to enable severe infection is lacking. Notably each of these risk factors pathologically disrupts the lipidome and this disruption may be a unifying feature of severe COVID-19.1-7 Here we provide the first in depth interrogation of lipidomic changes, including structural-lipids as well as the eicosanoids and docosanoids lipid mediators (LMs), that mark COVID-19 disease severity. Our data reveal that progression from moderate to severe disease is marked by a loss of specific immune regulatory LMs and increased pro-inflammatory species. Given the important immune regulatory role of LMs, these data provide mechanistic insight into the immune balance in COVID-19 and potential targets for therapy with currently approved pharmaceuticals.8
Comparison of SARS-CoV-2 serological tests with different antigen targets
Authors: Coste Alix T. , Jaton Katia , Papadimitriou-Olivgeris Matthaios , Greub Gilbert , Croxatto Antony
Published: July 2020

Background

These last months, dozens of SARS-CoV-2 serological tests have become available with varying performances. A major effort was completed to compare 17 serological tests.

Methods

In a preliminary phase, we compared 17 IgG, IgM, IgA and pan Ig serological tests including ELISA, LFA, CLIA and ECLIA on a panel of 182 sera, comprising 113 sera from hospitalized patients with a positive RT-PCR, and 69 sampled before 1stNovember 2019, expected to give a positive and negative results, respectively. In a second phase, the five best performing and most available tests were further evaluated on a total of 582 sera (178 and 404 expected positive and negative, respectively), allowing the assessment of 20 possible cross-reactions with other virus.

Results

In the preliminary phase, among eight IgG/pan-Ig ELISA or CLIA/ECLIA tests, four had a sensitivity and specificity above 90% and 98% respectively, and on six IgM/IgA tests, only one was acceptable. Only one LFA test on three showed good performances for both IgG and IgM. For all the tests IgM and IgG aroused concomitantly. In the second phase, no tests showed particular cross-reaction. We observed an important heterogeneity in the development of the antibody response, and that anti-nucleocapside (anti-N) antibodies appeared earlier than the anti-spike (anti-S) proteins.

Conclusions

The identified SARS-CoV-2 serology tests may be used for the diagnostic of CoviD-19 for negative RT-PCR patients presenting severe to mild suggestive symptoms or particular clinical presentation. Detection of both anti-N and anti-S could be complementary to increase the sensitivity of the analysis.
Long-Read cDNA Sequencing Enables a “Gene-Like” Transcript Annotation of Transposable Elements
Authors: Panda Kaushik , Slotkin R. Keith
Published: July 2020

Transcript-based annotations of genes facilitate both genome-wide analyses and detailed single-locus research. In contrast, transposable element (TE) annotations are rudimentary, consisting of information only on TE location and type. The repetitiveness and limited annotation of TEs prevent the ability to distinguish between potentially functional expressed elements and degraded copies. To improve genome-wide TE bioinformatics, we performed long-read sequencing of cDNAs from Arabidopsis (Arabidopsis thaliana) lines deficient in multiple layers of TE repression. These uniquely mapping transcripts were used to identify the set of TEs able to generate polyadenylated RNAs and create a new transcript-based annotation of TEs that we have layered upon the existing high-quality community standard annotation. We used this annotation to reduce the bioinformatic complexity associated with multimapping reads from short-read RNA sequencing experiments, and we show that this improvement is expanded in a TE-rich genome such as maize (Zea mays). Our TE annotation also enables the testing of specific standing hypotheses in the TE field. We demonstrate that inaccurate TE splicing does not trigger small RNA production, and the cell more strongly targets DNA methylation to TEs that have the potential to make mRNAs. This work provides a transcript-based TE annotation for Arabidopsis and maize, which serves as a blueprint to reduce the bioinformatic complexity associated with repetitive TEs in any organism.
Feasibility study of interferometric phase-contrast X-ray imaging using the hard-X-ray free-electron laser of the SPring-8 Angstrom Compact Free-Electron Laser
Authors: Yoneyama Akio , Baba Rika , Takamatsu Daiko , Kamezawa Chika , Inoue Ichiro , Osaka Taito , Owada Shigeki , Yabashi Makina
Published: July 2020

Aiming for the fine observation of fast physical phenomena such as phonon propagation and laser ablation, phase-contrast X-ray imaging combined with a crystal X-ray interferometer and the X-ray free-electron laser (XFEL) of the SPring-8 Angstrom Compact Free-Electron Laser has been developed. An interference pattern with 70% visibility was obtained by single-shot exposure with a 15 keV monochromated XFEL. In addition, a phase map of an acrylic wedge was successfully obtained using the fringe scanning method.
Crystal structure, Hirshfeld surface analysis and DFT study of 6-bromo-3-(5-bromohexyl)-2-[4-(dimethylamino)phenyl]-3H-imidazo[4,5-b]pyridine
Authors: Jabri Zainab , Sebbar Nada Kheira , Hökelek Tuncer , Mague Joel T. , Sabir Safia , Rodi Youssef Kandri , Misbahi Khalid
Published: July 2020

In the title molecule, C20H24Br2N4, the imidazopyridine moiety is not planar as indicated by the dihedral angle of 2.0 (2)° between the constituent rings; the 4-dimethylaminophenyl ring is inclined to the mean plane of the imidazole ring by 27.4 (1)°. In the crystal, two sets of C—H...π(ring) interactions form stacks of molecules extending parallel to the a-axis direction. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H...H (42.2%), H...C/C...H (23.1%) and H...Br/Br...H (22.3%) interactions. The optimized structure calculated using density functional theory (DFT) at the B3LYP/ 6–311 G(d,p) level is compared with the experimentally determined structure in the solid state. The calculated HOMO–LUMO energy gap is 2.3591 eV.
(2-Hydroxyphenyl)(4,2′:4′,4′′-terpyridin-6′-yl)methanone
Authors: Devika S. , Begum Noor Shahina , Manjappa Kiran B. , Yang Ding-Yah
Published: July 2020

The title compound, C22H15N3O2, can be described as a ketone with a phenol substituent and a terpyridine ligand coordinated to the carbonyl group. The three six-membered rings of the terpyridine ligand are not coplanar. The dihedral angles between the mean planes of the central ring and the external pyridine ligands are 22.77 (9) and 26.77 (7)°. The central ring of the terpyridine ligand is also not coplanar with the o-hydroxy phenyl ring, the dihedral angle being 39.72 (5)°. An intramolecular O—H...O hydrogen bond occurs. The crystal structure of the title compound is consolidated by C—H...O and C—H...N hydrogen bonding interactions.
Delivery mechanism on homeownership education among millennials in Kuala Lumpur
Authors: Zyed Zafirah Al Sadat , Low Chooi Sien , Tedong Peter Aning
Published: July 2020

Purpose

Millennials are considered the best group to intervene in terms of homeownership education as they are of working age and can earn monthly income. However, there is a concern about the affordability of millennials to purchase a house that will influence their decision in terms of purchasing a house. Further understanding of the home-buying process allows millennials to avoid dishonest and irresponsible sellers, as purchasing a house involves a large sum of money. The purpose of this study is to suggest a suitable delivery mechanism to increase awareness of the home-buying process among millennials in Kuala Lumpur.

Design/methodology/approach

This study adopts a quantitative method to analyse sets of questionnaire survey that were distributed at purposive random sampling in Kuala Lumpur. This study approached respondents with pre-set criteria, which include the respondents to be between 18 and 38 years old, interested to purchase a house and to have at least an initiatory understanding of the home-buying process.

Findings

The findings suggested that there is considerably low awareness of the home-buying process among millennials. However, it is important to note that among the home-buying process, millennials are most aware in the preliminary phase, which is information gathering. Based on these findings, the best delivery mechanism to increase awareness is through online games and training courses, followed by home counselling at a local housing agency.

Practical implications

This study contributes to government agencies and policymakers to interact with society, as education is one of the best methods. It will further enhance their efforts to ensure that the society is well equipped with useful knowledge to avoid the rueful decision of purchasing their first house.

Originality/value

This paper highlights homeownership education by tackling the issue of extensive knowledge of the home-buying process. This is crucial to the foundation of homeownership education, as it reflects the efforts of government agencies and policymakers to ensure homebuyers’ rights are protected in the housing market. This paper will benefit not only policymakers and decision-makers but also first time homebuyers.
Workplace ostracism and work-to-family conflict among female employees: moderating role of perceived organisational support
Authors: Choi Youngkeun
Published: July 2020

Purpose

Based on the conservation of resources theory, this study aims to develop and test the relationship between workplace ostracism and the work-to-family conflict of a female employee. And, it assumes that the direct link between workplace ostracism and the work-to-family conflict of a female employee is moderated by perceived organizational support.

Design/methodology/approach

For this, this study used a survey method and multiple regression analyses with multi-source data from 226 Korean female employees.

Findings

The results suggest the following. First, workplace ostracism was positively associated with the work-to-family conflict of a female employee. Second, there was a stronger positive relationship between workplace ostracism and work-to-family conflict for female employees with low as opposed to those with high levels of perceived organizational support.

Originality/value

To the best of author’s knowledge, this study is the first one to examine the moderating effect of perceived organizational support on the relationship between workplace ostracism and the work-to-family conflict of a female employee.
Firm collaborative capability and new product development performance: the mediating role of heterogeneous knowledge acquisition
Authors: Zhang Feng , Zhu Lei
Published: July 2020

Purpose

From the dynamic capability perspective, the aim of this paper is to develop a conceptual framework for collaborative capability, including scanning, relational skills and adaptation and to test the impact of each dimension on the acquisition of technological and marketing knowledge from partners. The conceptual framework also suggests that these two types of knowledge acquisition have different impacts on new product development (NPD) creativity and speed.

Design/methodology/approach

This study builds a theoretical framework and tests it with survey data from 289 Chinese manufacturing firms.

Findings

Firms with strong collaborative capability are identified to gain better knowledge acquisition from their partners and achieve higher NPD performance. While acquired technological knowledge has a greater effect on NPD creativity than acquired marketing knowledge, the latter has a greater effect on NPD speed. In addition, these two types of knowledge acquisition form different mediating paths between collaborative capability and NPD performance.

Practical implications

This study not only underlines the important role of collaborative capability in facilitating knowledge acquisition, which in turn improves NPD performance, but also suggests that decision-makers should note the different roles of technological knowledge and market knowledge in influencing NPD performance.

Originality/value

These findings enrich the understanding of how firms enhance NPD performance by developing collaborative capability in a major emerging economy (i.e. China). In addition to demonstrating the differential effects of heterogeneous knowledge acquisition on NPD performance, different pathways of mediation through knowledge acquisition are also identified in the relationship between collaborative capability and NPD outcomes.
The nature of individual experiential knowledge in internationalizing SMEs: pitfalls of superstitious learning and the need for wisdom
Authors: Hånell Sara Melén , Rovira Nordman Emilia , Mattsson Lars-Gunnar
Published: July 2020

Purpose

This study addresses the research question: How does the experiential knowledge, superstitious knowledge and the wisdom of CEOs influence the internationalization behaviour of SMEs?

Design/methodology/approach

An exploratory qualitative study is used. Longitudinal case studies of two Swedish life science companies are analysed.

Findings

An individual's prior experiential knowledge influence the newly started SME's market commitments and internationalization behaviour. Such prior experiences can enable early and rapid resource commitments in the newly started SMEs. Relying upon such prior experiential knowledge in deciding upon the company's market commitments however heightens the risk of superstitious learning. The findings illustrate how wisdom can work as an antidote to superstitious learning. Wisdom lures even experienced CEOs away from believing they know more than they actually know.

Research limitations/implications

The study contributes to extend the Uppsala model by incorporating the role of individual-level experiential knowledge. The study also adds value to the literature on small firm internationalization by providing propositions for how the prior knowledge of individual key decision makers influences SMEs' internationalization behaviour. The propositions provide new input to the ongoing discussion in the literature and help to guide future research.

Originality/value

Given the fact that the Uppsala model is centred upon a firm-level view on experiential knowledge, our theoretical understanding is still limited regarding how individual-level experiential knowledge influences the internationalization behaviour of SMEs. This study addresses calls for research on how individuals' prior knowledge influences small-firm internationalization.
An integrated decision-making model for supplier evaluation in public healthcare system: the case study of a Spanish hospital
Authors: Yazdani Morteza , Torkayesh Ali Ebadi , Chatterjee Prasenjit
Published: July 2020

Purpose

In this study, an integrated decision-making model consisting of decision-making trial and evaluation laboratory (DEMATEL), best worst method (BWM) and a modified version of evaluation based on distance from average solution (EDAS) methods is proposed for supplier selection problem in a public procurement system considering sustainable development goals.

Design/methodology/approach

DEMATEL and BWM methods are used to determine weights of the criteria that are defined for the supplier selection problem. Weight aggregation method is applied to combine the weights obtained from these two methods. A modified version of EDAS method is then used in order to rank the alternative suppliers.

Findings

The proposed decision-making model is investigated for a supplier selection problem for a hospital in Spain. The validity of the results is checked using comparison with other decision-making methods and several performance analysis tests.

Practical implications

The proposed multi-criteria decision-making (MCDM) model contributes to the healthcare supply chain management (SCM) and aims to lead the policy makers in selecting the best supplier.

Originality/value

There is no such study that combines DEMATEL and BWM together for weight generation. The application of the modified EDAS method is also new. In real time situations, the decision experts may confront to the difficulty of using BWM while identifying the best and the worst criteria choices. The idea of using DEMATEL is to aid the experts to make them enable in distinguishing between the best/worst criteria and handle BWM easily.