bluuebunny/crossref_metadata_2025 huggingface dataset:
Conjunctival Epithelial Ingrowth After Penetrating Keratoplasty
Authors: Hata-Mizuno Miki , Ingaki Emi , Mitamura Hiroto , Uchino Yuichi , Tsubota Kazuo , Shimmura Shigeto
Published: April 2020

Purpose:

To report a case of conjunctival epithelial ingrowth after penetrating keratoplasty.

Methods:

A 57-year-old woman with herpetic corneal keratitis, endotheliitis, and bullous keratopathy underwent penetrating keratoplasty (PKP) and secondary cataract surgery. One month after cataract surgery, an epithelial ingrowth was observed at the 5 o'clock donor host junction. Ingrowth extended into the anterior chamber and along the iris surface by 9 months. Another PKP was performed, and the excised graft was submitted for histopathology.

Results:

The graft showed CK13-positive and CK3-negative cells lining the endothelial surface, indicating the conjunctival origin of ingrown epithelium. Ten months postoperatively, no recurrence of ingrowth was observed.

Conclusions:

We experienced a rare case of conjunctival epithelial ingrowth after penetrating keratoplasty. There was no recurrence of the ingrowth after surgical removal, and the conjunctival origin may explain the relatively benign course of the complication.
Readiness to Return to Sport After ACL Reconstruction: A Combination of Physical and Psychological Factors
Authors: Cheney Sarah , Chiaia Theresa A. , de Mille Polly , Boyle Caroline , Ling Daphne
Published: April 2020

Although the incidence of anterior cruciate ligament injuries continues to rise, return to sport (RTS) rates remain low and risk of the second injury remains high. No gold-standard criteria exist for medical clearance to RTS after anterior cruciate ligament reconstruction. The lack of consensus may be driven by the multifactorial nature of the clinical decision that includes a combination of physical and psychological factors. Tools such as the Quality of Movement Assessment, which identifies physical deficits and faulty movement patterns to provide targeted recommendations for safe RTS, and the Anterior Cruciate Ligament Return to Sport after Injury Scale, which determines psychological readiness by measuring an athlete’s emotions, confidence, and risk appraisal, have been developed in recent years. This review summarizes the existing evidence regarding RTS and highlights the need for a comprehensive evaluation of an athlete’s readiness to return.
Biological Augmentation of ACL Repair and Reconstruction: Current Status and Future Perspective
Authors: Uchida Ryohei , Jacob George , Shimomura Kazunori , Horibe Shuji , Nakamura Norimasa
Published: April 2020

Historically, anterior cruciate ligament (ACL) suture repair mostly resulted in failure because of intra-articular hypovascularity and poor intrinsic healing capacity of ACL. ACL reconstruction was therefore deemed the gold standard with a high success rate because of more evolved surgical technique. There are, however, clinical and subclinical disadvantages of reconstruction; low rate in full recovery to sports, donor harvest morbidity, tunnel enlargement, and incomplete microscopic healing of the graft. Recent experimental and clinical studies on biological augmentation of mesenchymal stem cells, platelet-rich plasma, or the other biologic agents with scaffold suggested potential feasibility of positive effects by such bio-therapies for both ACL repair and reconstruction. Biological augmentation of ACL surgery is still in the exploratory stages and more evidence from preclinical and clinical studies is required for implementation in clinical practice.
Techniques for Femoral Socket Creation in ACL Reconstruction
Authors: Matthewson Graeme , Macdonald Peter
Published: April 2020

Anterior cruciate ligament (ACL) injury is common and affects a wide variety of individuals. An ACL reconstruction is the treatment of choice for patients with subjective and objective symptoms of instability and is of particular importance to cutting or pivoting athletes. With many variables involved in ACL reconstruction, femoral tunnel placement has been found to affect clinical outcomes with nonanatomic placement being identified as the most common technical error. Traditionally the femoral tunnel was created through the tibial tunnel or transtibial with the use of a guide and a rigid reaming system. Because of proximal, nonanatomic tunnel placement using the transtibial technique, the use of the anteromedial portal and outside-in drilling techniques has allowed placement of the tunnel over the femoral footprint. In this paper, we discuss the difference between the 3 techniques and the advantages and disadvantages of each. The authors then explore the clinical differences and outcomes in techniques by reviewing the relevant literature.
Automated quantification of tissue red blood cell perfusion as a new resuscitation target
Authors: Hilty Matthias P. , Ince Can
Published: April 2020

Purpose of review

Identification of insufficient tissue perfusion is fundamental to recognizing circulatory shock in critically ill patients, and the primary target to restore adequate oxygen delivery. However, the concept of tissue perfusion remains ill-defined and out-of-reach for clinicians as point-of-care resuscitation target. Even though handheld vital microscopy (HVM) provides the technical prerequisites to collect information on tissue perfusion in the sublingual microcirculation, challenges in image analysis prevent quantification of tissue perfusion and manual analysis steps prohibit point-of-care application. The present review aims to discuss recent advances in algorithm-based HVM analysis and the physiological basis of tissue perfusion-based resuscitation parameters.

Recent findings

Advanced computer vision algorithm such as MicroTools independently quantify microcirculatory diffusion and convection capacity by HVM and provide direct insight into tissue perfusion, leading to our formulation a functional parameter, tissue red blood cell (RBC) perfusion (tRBCp). Its definition is discussed in terms of the physiology of oxygen transport to the tissue and its expected effect as a point-of-care resuscitation target. Further refinements to microcirculatory monitoring include multiwavelength HVM techniques and maximal recruitable microcirculatory diffusion and convection capacity.

tRBCp as measured using algorithm-based HVM analysis with an automated software called MicroTools, represents a promising candidate to assess microcirculatory delivery of oxygen for microcirculation-based resuscitation in critically ill patients at the point-of-care.
Up-front Treatment With Romiplostim in Children With Acquired Bone Marrow Failure: A Single Institutional Pediatric Case Series
Authors: Al-Huniti Ahmad , Rathi Nityam , Modi Arun , Bhagavathi Sharathkumar , Mitten Roxane , Sharathkumar Anjali A.
Published: April 2020

Background:

Thrombopoietin receptor agonists are emerging as a therapeutic option for patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). We report our experience of treating children with AA/MDS with romiplostim, thrombopoietin receptor agonist.

Observations:

Three children (AA, 2; MDS, 1) received romiplostim treatment at a median dose of 10 μg/kg/week (starting dose: 5 μg/kg/wk; 2.5 μg/kg/wk increment). Trilineage hematopoietic recovery occurred at a median of 13 weeks (range: 13 to 16 wk) without adverse events. Hematopoiesis continued to improve after therapy discontinuation (median follow-up: 2.8 y; range: 0.5 to 3.0).

Conclusion:

Our experience supports the short-term safety and efficacy of romiplostim in children with AA/MDS.
Delayed Radiation Myelopathy in a Child With Hodgkin Lymphoma and ARTEMIS Mutation
Authors: Kara Buket , Seher Nusret , Ucaryilmaz Hulya , Yavas Guler , Paksoy Yahya , Artac Hasibe , Stray-Pedersen Asbjørg , Koksal Yavuz
Published: April 2020

The authors present a case of delayed radiation myelopathy in a 12-year-old girl with Hodgkin lymphoma and Artemis mutation. This is the first of such a case presented in the literature.
Prevalence Study of PD-L1 SP142 Assay in Metastatic Triple-negative Breast Cancer
Authors: Li Yijin , Vennapusa Bharathi , Chang Ching-Wei , Tran David , Nakamura Rin , Sumiyoshi Teiko , Hegde Priti , Molinero Luciana
Published: April 2020

Metastatic triple-negative breast cancer (mTNBC) is the most aggressive breast cancer subtype. Programmed death ligand 1 (PD-L1) on immune cells (IC) using the VENTANA SP142 assay is linked to improved clinical outcome in atezolizumab plus nab—paclitaxel-treated patients with mTNBC in the IMpassion130 study. The goal of the current study was to evaluate prevalence of VENTANA SP142 PD-L1 assay by anatomic location in 670 histologically confirmed TNBC cases from subjects with metastatic disease screened for the phase 1 study PCD4989g (NCT01375842). PD-L1 immunohistochemistry was centrally tested on tumor cells (TC) and on tumor infiltrating IC, following manufacturer’s instructions. At a 1% cutoff, tumor PD-L1 was more prevalent in IC than TC: 46% were PD-L1 IC+/TC−, 3% were PD-L1 IC−/TC+, and 10% were PD-L1 IC+/TC+. PD-L1 IC and TC immunostaining correlated with CD274 RNA expression, as assessed by fluidigm. Analyses of anatomic locations suggest that prevalence of PD-L1 IC+ was highest in lymph nodes (65.0%), lowest in liver metastases (26.9%), while breast tissue was intermediate (57.1%). Matched paired samples from the same subject collected synchronously or asynchronously showed a PD-L1 IC status agreement of 80% (8/10) and 75% (15/20), respectively. Our results suggest that the anatomic location of metastases and time of collection may influence the detection of PD-L1.
Prediction of Pediatric Critical Care Resource Utilization for Disaster Triage*
Authors: Killien Elizabeth Y. , Mills Brianna , Errett Nicole A. , Sakata Vicki , Vavilala Monica S. , Rivara Frederick P. , Kissoon Niranjan , King Mary A.
Published: April 2020

Objectives:

Pediatric protocols to guide allocation of limited resources during a disaster lack data to validate their use. The 2011 Pediatric Emergency Mass Critical Care Task Force recommended that expected duration of critical care be incorporated into resource allocation algorithms. We aimed to determine whether currently available pediatric illness severity scores can predict duration of critical care resource use.

Design:

Retrospective cohort study.

Setting:

Seattle Children’s Hospital.

Patients:

PICU patients admitted 2016–2018 for greater than or equal to 12 hours (n = 3,206).

Interventions:

None.

Measurements and Main Results:

We developed logistic and linear regression models in two-thirds of the cohort to predict need for and duration of PICU resources based on Pediatric Risk of Mortality-III, Pediatric Index of Mortality-3, and serial Pediatric Logistic Organ Dysfunction-2 scores. We tested the predictive accuracy of the models with the highest area under the receiver operating characteristic curve (need for each resource) and R
2 (duration of use) in a validation cohort of the remaining one of three of the sample and among patients admitted during one-third of the sample and among patients admitted during surges of respiratory illness. Pediatric Logistic Organ Dysfunction score calculated 12 hours postadmission had higher predictive accuracy than either Pediatric Risk of Mortality or Pediatric Index of Mortality scores. Models incorporating 12-hour Pediatric Logistic Organ Dysfunction score, age, Pediatric Overall Performance Category, Pediatric Cerebral Performance Category, chronic mechanical ventilation, and postoperative status had an area under the receiver operating characteristic curve = 0.8831 for need for any PICU resource (positive predictive value 80.2%, negative predictive value 85.9%) and area under the receiver operating characteristic curve = 0.9157 for mechanical ventilation (positive predictive value 85.7%, negative predictive value 89.2%) within 7 days of admission. Models accurately predicted greater than or equal to 24 hours of any resource use for 78.9% of patients and greater than or equal to 24 hours of ventilation for 83.1%. Model fit and accuracy improved for prediction of resource use within 3 days of admission, and was lower for noninvasive positive pressure ventilation, vasoactive infusions, continuous renal replacement therapy, extracorporeal membrane oxygenation, and length of stay.

Conclusions:

A model incorporating 12-hour Pediatric Logistic Organ Dysfunction score performed well in estimating how long patients may require PICU resources, especially mechanical ventilation. A pediatric disaster triage algorithm that includes both likelihood for survival and for requiring critical care resources could minimize subjectivity in resource allocation decision-making.
Diffusion-Tensor Imaging of Uterine Cervical Carcinoma: Correlation With Histopathologic Findings
Authors: Yamada Ichiro , Oshima Noriko , Wakabayashi Akira , Miyasaka Naoyuki , Wakana Kimio , Saida Yukihisa , Tateishi Ukihide , Kobayashi Daisuke
Published: April 2020

The authors investigated the usefulness of diffusion-tensor imaging (DTI) for evaluating tumor invasion depth, histologic grade, and lymph node metastasis in patients with cervical carcinoma (CC). Fifteen consecutive patients with histologically confirmed CC underwent 1.5-T magnetic resonance imaging and DTI. The CCs were clearly depicted as hypointense areas on all DTI maps. Fractional anisotropy, mean diffusivity, and axial diffusivity showed significantly inverse correlations with CC histologic grades and were significantly different between metastatic and nonmetastatic lymph nodes.
Liquid plasma reduces waste and health care expenses compared with thawed plasma at a Level I trauma center
Authors: Smith Sawyer , Dewey Elizabeth , VanSandt Mandy , Schreiber Martin
Published: April 2020

BACKGROUND

Balanced resuscitation strategies have led to increased utilization of plasma. Fresh frozen plasma that is thawed and never used is a large source of blood component wastage. Thawed plasma (TP) and can only be stored for 5 days. Liquid plasma (LP) has never been frozen and can be stored for 26 days. Due to longer storage duration, we hypothesized that using LP would result in decreased waste and cost savings compared with TP.

METHODS

We performed a retrospective review of all trauma patients at our Level I trauma center in the years 2015 to 2016. We compared 2015 when only TP was used to 2016 when both TP and LP were used. All plasma units ordered for trauma patients were tracked until the time of transfusion or wastage. Wastage rates were compared between years and plasma type.

RESULTS

There were 5,789 trauma patients admitted to our institution from 2015 to 2016. There were 4,107 plasma units ordered with 487 (11.9%) units wasted. During 2015, 2,021 total units of plasma were ordered with 273 (13.5%) units wasted which was a significantly higher rate than 2016 when 2,086 total units of plasma were ordered and 214 (10.3%) units were wasted (p = 0.0013). During 2016, 1,739 units of TP were ordered and 204 (11.7%) units were wasted which was significantly higher than LP wastage, 347 units ordered and 10 (2.9%) units wasted (p < 0.001). Of the 477 wasted TP units, 76.9% were ordered no more than two times before being wasted and 95.8% were ordered no more than three times before being wasted. Of the 10 LP units wasted, 40% were ordered no more than two times before being wasted, and 50% were ordered no more than three times before being wasted. If TP was wasted at the same rate as LP, 368 fewer units of plasma would have been wasted representing US $39,376 (US $107/unit) of wasted health care expenses.

CONCLUSION

At a Level I trauma center, the addition of LP to the blood bank for trauma resuscitations significantly reduced plasma wastage rates and health care expenses.

LEVEL OF EVIDENCE

Level III, Economic/Decision.
Attention allocation in a language with post-focal prominences
Authors: Ventura Caterina , Grice Martine , Savino Michelina , Kolev Diana , Brilmayer Ingmar , Schumacher Petra B.
Published: April 2020

Accentuation influences selective attention and the depth of semantic processing during online speech comprehension. We investigated the processing of semantically congruent and incongruent words in a language that presents cues to prosodic prominences in the region of the utterance occurring after the focussed information (the post-focal region). This language is Italian, in particular the variety spoken in Bari. In this variety, questions have a compressed, post-focal accent, whereas in statements there is a low-level pitch in this position. Using event-related potentials, we investigated the processing of congruent and incongruent target words with two prosodic realizations (focussed with accentuation, post-focal realization) and in two-sentence modalities (statement, question). Results indicate an N400 congruence effect that was modulated by position (focal, post-focal) and modality (statement, question): processing was deeper for questions in narrow focus than in post-focal position, while statements showed similar pronounced N400 effects across positions. The attenuated N400 difference for post-focal targets in questions was accompanied by a more enhanced late positivity when they were incongruent, indicating that attentional resources are allocated during updating of speech act information.
Resilient SARS-CoV-2 diagnostics workflows including viral heat inactivation
Authors: Lista Maria Jose , Matos Pedro M. , Maguire Thomas J. A. , Poulton Kate , Ortiz-Zapater Elena , Page Robert , Sertkaya Helin , Ortega-Prieto Ana M. , O’Byrne Aoife M. , Bouton Clement , Dickenson Ruth E , Ficarelli Mattia , Jimenez-Guardeño Jose M. , Howard Mark , Betancor Gilberto , Galao Rui Pedro , Pickering Suzanne , Signell Adrian W , Wilson Harry , Cliff Penelope , Tan Kia Ik Mark , Patel Amita , MacMahon Eithne , Cunningham Emma , Doores Katie , Agromayor Monica , Martin-Serrano Juan , Perucha Esperanza , Mischo Hannah E. , Shankar-Hari Manu , Batra Rahul , Edgeworth Jonathan , Zuckerman Mark , Malim Michael H. , Neil Stuart , Martinez-Nunez Rocio Teresa
Published: April 2020

There is a worldwide need for reagents to perform SARS-CoV-2 detection. Some laboratories have implemented kit-free protocols, but many others do not have the capacity to develop these and/or perform manual processing. We provide multiple workflows for SARS-CoV-2 nucleic acid detection in clinical samples by comparing several commercially available RNA extraction methods: QIAamp Viral RNA Mini Kit (QIAgen), RNAdvance Blood/Viral (Beckman) and Mag-Bind Viral DNA/RNA 96 Kit (Omega Bio-tek). We also compared One-step RT-qPCR reagents: TaqMan Fast Virus 1-Step Master Mix (FastVirus, ThermoFisher Scientific), qPCRBIO Probe 1-Step Go Lo-ROX (PCR Biosystems) and Luna® Universal Probe One-Step RT-qPCR Kit (Luna, NEB). We used primer-probes that detect viral N (EUA CDC) and RdRP (PHE guidelines). All RNA extraction methods provided similar results. FastVirus and Luna proved most sensitive. N detection was more reliable than that of RdRP, particularly in samples with low viral titres. Importantly, we demonstrate that treatment of nasopharyngeal swabs with 70 degrees for 10 or 30 min, or 90 degrees for 10 or 30 min (both original variant and B 1.1.7) inactivates SARS-CoV-2 employing plaque assays, and that it has minimal impact on the sensitivity of the qPCR in clinical samples. These findings make SARS-CoV-2 testing portable to settings that do not have CL-3 facilities. In summary, we provide several testing pipelines that can be easily implemented in other laboratories and have made all our protocols and SOPs freely available at https://osf.io/uebvj/.
Dataset on the COVID-19 Pandemic Situation in Tunisia with Application to SIR Model
Authors: Lassoued Abir , Saad Afef Ben , Lassoued Hela , Ketata Raouf , Boubaker Olfa
Published: April 2020

April 9, 2020 marks 100 days since the first cases of coronavirus disease 2019 in China. In this crucial day with 1 436 198 confirmed infected cases in the world and 85 521 deaths, the Global Level of the Covid-19 pandemic was evaluated at very high according to the World Health Organization (WHO) situation report. For most people, COVID-19 infection will cause mild illness (fever and at least one symptom of respiratory disease); however, for more than 3.4% of people, it can be fatal. Older people and those with preexisting medical conditions (such as cardiovascular disease, chronic respiratory disease, or diabetes) are at risk of severe disease and mortality. The incubation period of the virus is estimated to be between 2 and 14 days, but longer incubation had been reported. Furthermore, data published by world authorities show that statistics are different for different geographical regions and depend on many social and environmental factors. The sad reality of the COVID-19 is that there are currently no medications or vaccines proven to be effective for the treatment or prevention of the disease. The pandemic spread is consequenctly followed by a worldwide panic. Facing this dramatic uncertain situation, implementing a country-wide strategy for social distancing and a general logistic policy for critical and life-saving supplies is an urgent for government and sanitary authorities. Several mathematical models have been proposed to predict epidemic spread. However, models should be adapted to specific situations in countries where geographic, societal, economic, and political strategies are different. Here, we propose the application of the well-known SIR model to the case study of Tunisia for which data are collected from three databases in order to have rapidly predict the situation. Such results can be useful in the future to design a more reliable model to help in monitoring infection control.
An alternative model to prion fragmentation based on the detailed balance between PrPScand suPrP
Authors: Chyba Monique , Kotas Jakob , Beringue Vincent , Eblen Christopher , Igel-Egalon Angelique , Kravchenko Yuliia , Rezaei Human
Published: April 2020

Prion assemblies responsible for transmissible spongiform encephalopathies grow in the form of linear amyloid fibrils. Traditional models for prion growth and tissue-spreading have relied upon the assumption that propagation is based on the process of fragmentation, wherein an assembly literally breaks in two, creating additional templating interfaces. Recent experimental data shows that PrPScassemblies are in detailed balance with an elementary oligomeric building block called suPrP. In the present work we compare the dynamics of the canonical model of induced-fragmentation to the model of PrPScassemblies in detailed balance with suPrP. The model is a dynamical system describing the populations of fibrils of varying lengths as a function of time; we analyze the system via both analytical and numerical techniques. We demonstrate that the detailed balance between suPrP and PrPScmodel can equivalently replace the induced-fragmentation model. This equivalence opens a new opportunity in an optimal control problem.
Lung injury in patients with or suspected COVID-19 : a comparison between lung ultrasound and chest CT-scanner severity assessments, an observational study
Authors: Benchoufi Mehdi , Bokobza Jerôme , Chauvin Anthony , Dion Elisabeth , Baranne Marie-Laure , Levan Fabien , Gautier Maxime , Cantin Delphine , d’Humières Thomas , Gil-Jardiné Cédric , Benenati Sylvain , Orbelin Mathieu , Martinez Mikaël , Pierre-Kahn Nathalie , Diallo Abdourahmane , Vicaut Eric , Bourrier Pierre
Published: April 2020

Background

Chest CT (CT) is the reference for assessing pulmonary injury in suspected or diagnosed COVID-19 with signs of clinical severity. We explored the role of lung ultrasonography (LU) in quickly assessing lung status in these patients.

Methods

eChoVid is a multicentric study based on routinely collected data, conducted in 3 emergency units of Assistance Publique des Hôpitaux de Paris (APHP); 107 patients were included between March 19, 2020 and April 01, 2020 and underwent LU, a short clinical assessment by 2 emergency physicians blinded to each other’s and a CT. LU consisted of scoring lesions in 8 chest zones from 0 to 3, defining a severity global score (GS) ranging from 0 to 24. CT severity score ranged from 0 to 3 according to the extent of interstitial pneumonia signs. 48 patients underwent LU by both an expert and a newly trained physician.

Findings

The GS showed good performance to predict CT severity assessment of COVID-19 as normal versus pathologic: AUC=0.93, maximal Youden index 1 with 95% sensitivity, and 83% specificity. Similar performance was found for CT assessment as normal or minimal versus moderate or severe (n=90): AUC 0.89, maximal Youden index 7 with 86% sensitivity, and 78% specificity. Good agreement was found for zone scoring assessed by new trainee (30mn theory + 30mn practice) and expert (n=14,14*8 checkpoints), weighted kappa 0.85-1; moderate agreement was found for new trainee (n=48, 30mn theory) and expert, kappa 0.62-0.81.

Interpretation

GS score is a simple tool to assess lung damage severity in patients with suspected or diagnosed COVID-19. Comparing the performance of new trainees and expert physicians opens a path for adoption beyond the scope of experts. LU is a good candidate for patients triage, especially in case of CT availability issues.
Vitamin D insufficiency is prevalent in severe COVID-19
Authors: Lau Frank H. , Majumder Rinku , Torabi Radbeh , Saeg Fouad , Hoffman Ryan , Cirillo Jeffrey D. , Greiffenstein Patrick
Published: April 2020

Background

COVID-19 is a major pandemic that has killed more than 196,000 people. The COVID-19 disease course is strikingly divergent. Approximately 80-85% of patients experience mild or no symptoms, while the remainder develop severe disease. The mechanisms underlying these divergent outcomes are unclear. Emerging health disparities data regarding African American and homeless populations suggest that vitamin D insufficiency (VDI) may be an underlying driver of COVID-19 severity. To better define the VDI-COVID-19 link, we determined the prevalence of VDI among our COVID-19 intensive care unit (ICU) patients.

Methods

In an Institutional Review Board approved study performed at a single, tertiary care academic medical center, the medical records of COVID-19 patients were retrospectively reviewed. Subjects were included for whom serum 25-hydroxycholecalcifoerol (25OHD) levels were determined. COVID-19-relevant data were compiled and analyzed. We determined the frequency of VDI among COVID-19 patients to evaluate the likelihood of a VDI-COVID-19 relationship.

Results

Twenty COVID-19 patients with serum 25OHD levels were identified; 65.0% required ICU admission.The VDI prevalence in ICU patients was 84.6%, vs. 57.1% in floor patients. Strikingly, 100% of ICU patients less than 75 years old had VDI. Coagulopathy was present in 62.5% of ICU COVID-19 patients, and 92.3% were lymphocytopenic.

Conclusions

VDI is highly prevalent in severe COVID-19 patients. VDI and severe COVID-19 share numerous associations including hypertension, obesity, male sex, advanced age, concentration in northern climates, coagulopathy, and immune dysfunction. Thus, we suggest that prospective, randomized controlled studies of VDI in COVID-19 patients are warranted.
CDC50A dependent phosphatidylserine exposure induces inhibitory post-synapse elimination by microglia
Authors: Park Jungjoo , Jung Eunji , Lee Seung-Hee , Chung Won-Suk
Published: April 2020

Glia contribute to synapse elimination through phagocytosis in the central nervous system. Despite important roles during development and neurological disorders, the “eat-me” signal that initiates glia-mediated phagocytosis of synapses remains largely elusive. Here, by generating inducible conditional knockout mice ofCdc50a, we induced stable exposure of phosphatidylserine in the neuronal outer membrane. Surprisingly, acuteCdc50adeletion in neurons causes specific loss of inhibitory post-synapses without affecting other synapses, thereby generating excessive excitability with appearance of seizure. Ablating microglia or deleting microglialMertkrescues the loss of inhibitory post-synapses, indicating that microglial phagocytosis is responsible for inhibitory post-synapse elimination. Moreover, inhibitory post-synapses in normal juvenile brains also use phosphatidylserine for synapse pruning by microglia, suggesting that phosphatidylserine may serve as a general “eat-me” signal for inhibitory post-synapse elimination.

One Sentence Summary

Cdc50adependent phosphatidylserine exposure functions as an “eat-me” signal for microglia-dependent inhibitory post-synapse elimination
RIT1: A Novel Biomarker in Glioblastoma
Authors: Khalil Athar , Nemer Georges
Published: April 2020

Glioblastoma is the most common type of malignant brain tumors and the most feared cancer among adults. Its high invasiveness and the lack of successful therapies are responsible for the poor prognosis among these patients. A comprehensive understanding for the early molecular mechanisms in glioblastoma would definitely enhance its diagnosis and treatment strategies. Based on in vitro and in vivo models, it was recently postulated that the deregulated expression of key genes that are known to be involved in early neurogenesis could be the instigator of brain tumorigenesis. RIT1 (Ras Like Without CAAX 1) which encodes an unusual “orphan” GTPase protein belongs to this category of critical genes involved in controlling sequential proliferation and differentiation of adult hippocampal neural progenitor cells. As such, we surveyedRIT1expression and its potential role in glioblastoma by in-silico means. Our results revealed a significant and progressive upregulation of RIT1 expression in various publicly available datasets.RIT1expression ranked among the top upregulated genes in glioblastoma cohorts and correlated with poor overall survival. Genetic and epigenetic analysis of RIT1 didn’t reveal significant aberrations that could underlie its deregulated expression. Moreover, our results pointed onRIT1transcriptional activity that could be significantly controlled by STAT3, one of the main players in the onset of glioblastoma. In conclusion, our results are the first proof for the role of RIT1 as an oncogene in glioblastoma paving the way for its potential use as a biomarker and therapeutic target as is the case of the other members in the RAS family.
PD-1 and PD-L1 are diagnostic biomarkers and PD-L1 a promising therapeutic target in HER2-positive and triple negative normal-like feline mammary carcinoma subtypes
Authors: Nascimento Catarina , Urbano Ana Catarina , Gameiro Andreia , Ferreira João , Correia Jorge , Ferreira Fernando
Published: April 2020

Tumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. In order to understand the role of the PD- 1/PD-L1 axis in cats with mammary carcinoma, serum PD-1 and PD-L1 levels were compared with healthy controls and with serum CTLA-4 and TNF-αlevels. PD-1 and PD-L1 expression was evaluated in TILs and cancer cells, as the presence of somatic mutations. Results showed that serum PD-1 and PD-L1 levels were significantly higher in cats with HER2-positive (p=0.017; p=0.032) and triple negative (TN) normal-like mammary carcinomas (p=0.004; p=0.015). Besides, cats presenting these tumor subtypes showed a strong positive correlation between serum PD-1, PD-L1, CTLA-4 and TNF-αlevels. In tumors, PD-L1 expression in cancer cells was significantly higher in HER2-positive samples than in TN normal-like tumors (p=0.010), as the percentage of PD-L1-positive TILs (p=0.038). Results from the PD-L1 gene sequencing identified two heterozygous mutations in exon 4 (A245T, 3.8%; V252M, 42.3%) and one in exon 5 (T267S, 3.8%). In summary, results support that serum PD-1 and PD-L1 levels can be used as diagnostic biomarkers of HER2-positive and TN normal-like feline mammary carcinomas and suggest that the development of monoclonal antibodies may be a good therapeutic strategy.
Improved estimation of hemodynamic response in fNIRS using protocol constraint and wavelet transform decomposition based adaptive algorithm
Authors: Jahani Sahar , Setarehdan Seyed Kamaledin
Published: April 2020

Background

Near infrared spectroscopy allows monitoring of oxy and deoxyhemoglobin concentration changes associated with hemodynamic response function (HRF). HRF is mainly affected by physiological interferences which occur in the superficial layers of the head. This makes HRF extracting a very challenging task. Recent studies have used an additional near channel which is sensitive to the systemic interferences of the superficial layers. This additional information can be used to remove the systemic interference from the HRF.

New Method

This paper presents a novel wavelet-based constrained adaptive procedure to define the proportion of the physiological interferences in the brain hemodynamic response. The proposed method decomposes the near channel signal into several wavelet transform (WT) scales and adaptively estimates proper weights of each scale to extract their share in the HRF. The estimation of the weights are done by applying data acquisition protocol as a coefficient on recursive least square (RLS), normalized least mean square (NLMS) and Kalman filter methods.

Results

Performance of the proposed algorithm is evaluated in terms of the mean square error (MSE) and Pearson’s correlation coefficient (R2) criteria between the estimated and the simulated HRF.

Comparison with Existing Methods

Results showed that using the proposed method is significantly superior to all past adaptive filters such as EMD/EEMD based RLS/NLMS on estimating HRF signals.

Conclusions

we recommend the use of WT based constraint Kalman filter in dual channel fNIRS studies with a defined protocol paradigm and using WT based Kalman filter in studies without any pre-defined protocol.
Deficiency in reverse cholesterol transport in mice augments sepsis
Authors: Wang Qian , Guo Ling , Hao Dan , Ito Misa , Yu Kai-jiang , Wang Rui-tao , Mineo Chieko , Shaul Philip W. , Li Xiang-An
Published: April 2020

Background

Sepsis claims over 215,000 lives and costs $16.7 billion per year in America alone. Recent studies revealed that HDL receptor scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. Using Scarb1I179N mice, a mutant SR-BI mouse model with 90% depletion in hepatic SR-BI, we previously reported that the mutant mice are susceptible to cecal ligation and puncture (CLP)-induced sepsis. However, using a hypo-AlbCreSR-BIfl/fl mouse model, Huby’s group showed that the liver-specific SR-BI KO mice are not more susceptible to CLP-induced sepsis. In this study, we generated a new floxed SR-BI mouse model to clarify the contribution of hepatic SR-BI in sepsis. SR-BI is known as a receptor that plays a key role in reverse cholesterol transport (RCT) by uptaking cholesterol to the liver. So, our established AlbCreSR-BIfl/fl mice (liver-specific SR-BI KO) is an RCT deficiency mice model that can be used to understand the mechanisms of RCT protecting against sepsis and may provide new insight into the pathogenesis of sepsis.

Methods and Results

We generated SR-BIfl/fl mice by flanking exon 2. We bred the floxed mice with AlbCre mice to generate AlbCreSR-BIfl/fl mice (liver-specific SR-BI KO mice), then the mice were backcrossed to C57BL/6J for 10 generations. As shown in Fig 1, the liver SR-BI expression was normal in SR-BIfl/fl mice as compared to C57BL/6J (B6) mice, but completely depleted in AlbCreSR-BIfl/fl mice. Using this liver-specific SR-BI KO model, we observed that a deficiency in RCT rendered the mice highly susceptible to CLP-induced sepsis as shown by 80% and 14.3% survival of SR-BIfl/fl and AlbCreSR-BIfl/fl mice, respectively. We found aggravated inflammatory cytokine production, altered leukocyte recruitment and slightly increased in the blood and peritoneal bacteria. Moreover, we found RCT deficiency mice increased both free and total cholesterol levels in serum and showed severer hemolysis in AlbCreSR-BIfl/fl mice than SR-BIfl/fl mice during CLP-induced sepsis. Importantly, when we fed AlbCreSR-BIfl/fl mice with probucol to decrease the cholesterol level in serum before performing CLP, the survival rate of AlbCreSR-BIfl/fl mice improved to 88.9%.

Conclusions

Deficiency RCT resulting in abnormal metabolism of cholesterol and lipid metabolism is a risk factor in sepsis and maintain normal metabolism of cholesterol may provide a new insight for sepsis therapies.
Detecting and Quantitating Low Fraction DNA Variants with Low-Depth Sequencing
Authors: Song Ping , Chen Sherry X. , Yan Yan Helen , Pinto Alessandro , Cheng Lauren Y. , Dai Peng , Patel Abhijit A. , Zhang David Yu
Published: April 2020

DNA sequence variants with low allele frequencies below 1% are difficult to detect and quantitate by sequencing, due to the intrinsic error of sequencing-by-synthesis (NGS). Unique molecular identifier barcodes can in principle help NGS detect mutations down to 0.1% variant allele frequency (VAF), but require extremely high sequencing depths of over 25,000x, rendering high sensitivity mutation detection out of reach for most research and clinical samples. Here, we present the multiplex blocker displacement amplification (mBDA) method to selectively enrich DNA variants by an average of 300-fold in highly multiplexed NGS settings. On a 80-plex human single nucleotide polymorphism panel, mBDA achieves a 0.019% VAF limit of detection for single nucleotide variants, using only 250x sequencing depth, and detects human cell line contamination down to 0.07%. Using this technology, we constructed a 16-plex melanoma NGS panel covering 145 actionable mutations across 9 genes, and applied it to 19 fresh/frozen tumor biopsy tissue samples with high tumor fractions. We found low VAF mutations (0.2% to 5%) in 37% of the samples (7/19, 95% confidence interval 19%-58%). These results suggest that tumor heterogeneity could be significantly more pervasive than previously recognized, and can contribute significantly to acquired drug resistance to targeted therapies. We also validate mBDA panels on clinical cell-free DNA samples from lung cancer patients.
Matrix factorization recovers consistent regulatory signals from disparate datasets
Authors: Sastry Anand V. , Hu Alyssa , Heckmann David , Poudel Saugat , Kavvas Erol , Palsson Bernhard O.
Published: April 2020

The availability of gene expression data has dramatically increased in recent years. This data deluge could result in detailed inference of underlying regulatory networks, but the diversity of experimental platforms and protocols introduces critical biases that could hinder scalable analysis of existing data. Here, we show that the underlying structure of theE. colitranscriptome, as determined by Independent Component Analysis (ICA), is conserved across multiple independent datasets, including both RNA-seq and microarray datasets. We also show that echoes of this structure remain in the proteome, accelerating biological discovery through multi-omics analysis. We subsequently combined five transcriptomics datasets into a large compendium containing over 800 expression profiles and discovered that its underlying ICA-based structure was still comparable to that of the individual datasets. ICA thus enables deep analysis of disparate data to uncover new insights that were not visible in the individual datasets.
NMR microsystem for label-free characterization of 3D nanoliter microtissues
Authors: Grisi Marco , Conley Gaurasundar M. , Rodriguez Kyle J. , Riva Erika , Egli Lukas , Moritz Wolfgang , Lichtenberg Jan , Brugger Jürgen , Boero Giovanni
Published: April 2020

Performing chemical analysis at the nanoliter (nL) scale is of paramount importance for medicine, drug development, toxicology, and research. Despite the numerous methodologies available, a tool for obtaining chemical information non-invasively is still missing at this scale. Observer effects, sample destruction and complex preparatory procedures remain a necessary compromise1. Among non-invasive spectroscopic techniques, one able to provide holistic and highly resolved chemical informationin-vivois nuclear magnetic resonance (NMR)2,3. For its renowned informative power and ability to foster discoveries and life-saving applications4,5, efficient NMR at microscopic scales is highly sought after6–10, but so far technical limitations could not match the stringent necessities of microbiology, such as biocompatible handling, ease of use, and high throughput. Here we introduce a novel microsystem, which combines CMOS technology with 3D microfabrication, enabling nL NMR as a platform tool for non-invasive spectroscopy of organoids, 3D cell cultures, and early stage embryos. In this study we show its application to microlivers models simulating non-alcoholic fatty liver disease (NAFLD), demonstrating detection of lipid metabolism dynamics in a time frame of 14 days based on 117 measurements of single 3D human liver microtissues.
Widespread variation in heat tolerance of the coralAcropora hyacinthusspanning variable thermal regimes across Palau
Authors: Cornwell Brendan , Hounchell Katrina , Walker Nia , Golbuu Yimnang , Nestor Victor , Palumbi Stephen R.
Published: April 2020

Climate change is poised to dramatically change ecosystem composition and productivity, leading scientists to consider the best approaches to fostering population resilience and diversity in the face of these changes. Here we present results of a large-scale experimental assessment of bleaching resistance, a critical trait for coral population persistence as oceans warm, in 293 colonies of the coralAcropora hyacinthusacross 39 reefs in Palau. We find bleaching resistant individuals originate significantly more often from warmer reefs, although they inhabit almost every reef regardless of temperature at low frequency. High levels of variationwithinreefs, where colonies experience similar temperatures, suggests that bleaching resistance is not solely due to phenotypic plasticity, but also involves adaptive alleles and host-symbiont interactions. To the extent that it is heritable, bleaching resistance could be used in promoting nursery growth, habitat restoration, or breeding, while employing large numbers of resistant colonies to preserve genetic variation.
A novel single-cell based method for breast cancer prognosis
Authors: Li Xiaomei , Liu Lin , Goodall Greg , Schreiber Andreas , Xu Taosheng , Li Jiuyong , Le Thuc Duy
Published: April 2020

Breast cancer prognosis is challenging due to the heterogeneity of the disease. Various computational methods using bulk RNA-seq data have been proposed for breast cancer prognosis. However, these methods suffer from limited performances or ambiguous biological relevance, as a result of the neglect of intra-tumor heterogeneity. Recently, single cell RNA-sequencing (scRNA-seq) has emerged for studying tumor heterogeneity at cellular levels. In this paper, we propose a novel method,scPrognosis, to improve breast cancer prognosis with scRNA-seq data.scPrognosisuses the scRNA-seq data of the biological process Epithelial-to-Mesenchymal Transition (EMT). It firstly infers the EMT pseudotime and a dynamic gene co-expression network, then uses an integrative model to select genes important in EMT based on their expression variation and differentiation in different stages of EMT, and their roles in the dynamic gene co-expression network. To validate and apply the selected signatures to breast cancer prognosis, we use them as the features to build a prediction model with bulk RNA-seq data. The experimental results show thatscPrognosisoutperforms other benchmark breast cancer prognosis methods that use bulk RNA-seq data. Moreover, the dynamic changes in the expression of the selected signature genes in EMT may provide clues to the link between EMT and clinical outcomes of breast cancer.scPrognosiswill also be useful when applied to scRNA-seq datasets of different biological processes other than EMT.

Author summary

Various computational methods have been developed for breast cancer prognosis. However, those methods mainly use the gene expression data generated by the bulk RNA sequencing techniques, which average the expression level of a gene across different cell types. As breast cancer is a heterogenous disease, the bulk gene expression may not be the ideal resource for cancer prognosis. In this study, we propose a novel method to improve breast cancer prognosis using scRNA-seq data. The proposed method has been applied to the EMT scRNA-seq dataset for identifying breast cancer signatures for prognosis. In comparison with existing bulk expression data based methods in breast cancer prognosis, our method shows a better performance. Our single-cell-based signatures provide clues to the relation between EMT and clinical outcomes of breast cancer. In addition, the proposed method can also be useful when applied to scRNA-seq datasets of different biological processes other than EMT.
Generation of kidney ureteric bud and collecting duct organoids that recapitulate kidney branching morphogenesis
Authors: Zeng Zipeng , Huang Biao , Parvez Riana K. , Li Yidan , Chen Jyunhao , Vonk Ariel , Thornton Matthew E. , Patel Tadrushi , Rutledge Elisabeth A. , Kim Albert D. , Yu Jingying , Pastor-Soler Nuria , Hallows Kenneth R. , Grubbs Brendan H. , McMahon Jill A. , McMahon Andrew P. , Li Zhongwei
Published: April 2020

Kidney organoids model development and diseases of the nephron but not the contiguous epithelial network of the kidney’s collecting duct (CD) system. Here, we report the generation of an expandable, 3D branching ureteric bud (UB) organoid culture model that can be derived from primary UB progenitors from mouse and human fetal kidneys, or generatedde novofrom pluripotent human stem cells. UB organoids differentiate into CD organoidsin vitro, with differentiated cell types adopting spatial assemblies reflective of the adult kidney collecting system. Aggregating 3D-cultured nephron progenitor cells with UB organoidsin vitroresults in a reiterative process of branching morphogenesis and nephron induction, similar to kidney development. Combining efficient gene editing with the UB organoid model will facilitate an enhanced understanding of development, regeneration and diseases of the mammalian collecting system.

One sentence summary

Collecting duct organoids derived from primary mouse and human ureteric bud progenitor cells and human pluripotent stem cells provide anin vitroplatform for genetic dissection of development, regeneration and diseases of the mammalian collecting system.