bluuebunny/crossref_metadata_2025 huggingface dataset:
OMRT-11. The effect of microenvironment on glioblastoma stem cells therapeutic resistance
Authors: Turnsek Tamara Lah , Breznik Barbara , Majc Bernarda , Novak Metka , Porčnik Andrej , Habič Anamarija , Mlinar Mateja , Bošnjak Roman
Published: July 2021

Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process in physiologic processes and invasion of various types of carcinoma and glioblastoma (GBM) cells. EMT is activated and regulated by specific endogenous triggers in complex network of intercellular interactions and signaling pathways. The hallmark of cancer-linked EMT are intermediate states that show notable cell plasticity, characteristic of cancer stem cells (CSCs), including glioblastoma stem cells – GSCs. GSCs resistance to irradiation (IR) and temozolomide (TMZ) chemotherapy is responsible for early relapses, even at distant brain sites. As GSCs are mostly homing to their “niches” as slowly-dividing GSC-subtype, mimicking a proneural-like non- invasive phenotype PN-genotype, we assume that this, by undergoing an EMT-like transition, GSCs are-reprogrammed to an invasive mesenchymal (MES) GBs/GSCs phenotype in a processes, called PMT (1). However, it is not known, if and by which environmental cues within the niche, this transition of GSCs is induced in vivo. In this work, we are presenting the transriptome data obtained when we exposed GSC spheroids to irradiation alone, TMZ alone and to the combined treatment in vitro and compared their differential genetic fingerprints related to EMT/PMT transition to the GSCs PMT transition, when embedded in their natural microenvironment in the GBM organoid model. The differential gene expression upon GSCs therapeutic perturbation (when alone and vs in the tumoroid microenvironment) will reveal the effects of the major candidate genes, associated with micronevironmendt stromal cells and matrix are contributing their observed EMT/PMT transition of GSCs in vivo.

•1. Majc, B., Sever, T., Zarić, M, Breznik, B., Turk, B, Lah Turnšek, T. Epithelial- to-mesenchymal transition as the driver of changing carcinoma and glioblastoma microenvironment. DOI: 10.1016/j.bbamcr.2020.118782
OMRT-13. Delivery of Ubidecarenone (BPM 31510) to mitochondria effectuates metabolic reprogramming and redox activated apoptosis in Glioblastoma
Authors: Sarangarajan Rangaprasad , Nagpal Seema , Sun Jiaxin , Diers Anne , Shah Punit , Tolstikov Vladimir , Miller Gregory , Vishnudas Vivek , Gesta Stephane , Kiebish Michael , Granger Elder , Narain Niven , Recht Lawrence
Published: July 2021

GBM is a highly metabolic cancer phenotype that confers sustained growth and evasion of cell death mechanism via mitochondrial dysregulation. Efforts to re-engage mitochondrial metabolism via anti-cancer therapeutics has not been successful. BPM 31510 is a CoQ10-lipid conjugate nanodispersion for delivery of CoQ10 preferentially to mitochondria of human cells. BPM has demonstrated anti-cancer effects across multiple cancers, without adversely affecting normal tissue. The anti-cancer mechanism of CoQ10 was elucidated by Interrogative Biology, a data-driven approach to understand disease biology, identify targets and biomarkers of disease. Specifically, oncogenic and corresponding non-disease normal cell-based models (e.g. breast, liver, prostate, kidney) were subjected to cancer specific perturbations (e.g. hypoxia, metabolic stress). Comprehensive multi-omic (genome, proteome, lipidome, metabolome) and functional endpoints data were profiled. A Bayesian artificial intelligence analytics was used to generate network models in a data driven manner to identify BPM 31510 mechanism (i.e. shift in oxygen and glucose utilization, increase in oxidative stress and apoptosis in cancer cells). BPM 31510 re-capitulated its anti-cancer effect in GBM models, including LN-229 xenograft and C6 glioma allograft, both as monotherapy and in combination with temozolomide (TMZ)/radiation. The platform generated network maps from longitudinal pharmacodynamic samples (20 samples/28 days) collected from GBM patient refractory to TMZ/radiation/bevacizumab (Phase 1, NCT03020602, Stanford) identified alterations in intermediary metabolism as drivers of Progression Free Survival (PFS) and Overall Survival (OS) in response to BPM 31510 treatment. The platform supports the ongoing Phase 2 trial of adjuvant BPM 31510 plus TMZ/radiation in newly diagnosed GBM patients and potential accelerated approval.
OTEH-2. High-dimensional analysis of spatial immune cell heterogeneity in glioblastoma reveals differences between contrast-enhancing and non-contrast-enhancing tumor rims
Authors: Watson Dionysios C , Bayik Defne , Grabowski Matthew , Ahluwalia Manmeet , Mohammadi Alireza , Lathia Justin D
Published: July 2021

Background

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. GBM remains an incurable disease, with a median survival ~20 months. Complex intercellular interactions within the tumor microenvironment and spatial heterogeneity have challenged and impeded therapeutic efficacy. The non-contrast-enhancing (by T1-weighted MRI) rim of GBM is not always safely resectable and represents a major source of recurrence. We hypothesized that differential immune infiltration is an underlying factor of spatial heterogeneity in GBM, particularly in the non-contrast-enhancing tumor rim.

Methods

Five patients with newly diagnosed GBM (ages 53–84) were recruited to a device feasibility study (NCT04545177) utilizing an intraoperative high-resolution MRI-based navigation system coupled with the NICO Myriad (a non-ablative semi-automated resection tool) and a coupled automated biological Tissue Preservation System (NICO APS) to sample spatially mapped regions of tumors in a reproducible and minimally destructive manner. We obtained brain tumor tissue from: (a) tumor core, (b) contrast-enhancing tumor rim and (c) non-contrast-enhancing tumor rim. Downstream processing consisted of digestion of tumor tissue (Miltenyi human tumor digestion kit) for subsequent single-cell isolation, viability assessment and immediate staining for multiparametric flow cytometry for immune profiling.

Results

Viability varied across sampled regions (median 85%, range 52–100%). With the exception of 1 sample, viability was >70% in all specimens. High-dimensional analysis with 26 marker flow cytometry revealed spatial heterogeneity in the frequency of myeloid-derived suppressor cell subsets, regulatory T cells, CD8+ T cells, as well as expression of T cell activation and exhaustion markers.

Conclusions

Semi-automated, spatially mapped intraoperative sampling of GBM with high viability of specimens is feasible and reproducible with the NICO Myriad and APS devices. High-dimensional analysis of immune cells in the GBM microenvironment captured the spatial heterogeneity of GBM. Future studies will expand on these observations by analyzing more patient specimens in combination with multiple omics assays.
OTME-11. Characterizing the immunologic context of pediatric brain tumors
Authors: Galvin Robert , Maeser Danielle , Gruener Robert , Huang R Stephanie
Published: July 2021

Therapy for pediatric central nervous system (CNS) malignancies can be toxic, and outcomes are suboptimal. Immunotherapy holds promise as a therapeutic avenue, but the poorly understood microenvironment limits its application. The Children’s Brain Tumor Network (CBTN) released the Pediatric Brain Tumor Atlas, containing expression profiles of nearly 700 primary CNS tumors. To study the immune microenvironment, a classification from The Cancer Genome Atlas project is applied. High-grade lesions are predominantly lymphocyte deplete (C4, 81%) or immunologically quiet (C5, 11%). Low-grade lesions are more mixed with 46% C4, 21% C5, and a higher proportion of inflammatory subtype (C3, 31%). For survival parameters, adjusting for tumor grade and extent of resection, the hazard ratio is 2.2 (0.78 – 6.3), p = 0.13) and 2.4 (0.6 – 10.0, p = 0.24) for C4 and C5, respectively. With no events among low-grade tumors, progression-free survival will be another useful metric and released by CBTN in April. Deconvolution of immune cell gene signatures among C4 samples reveals decreased abundance of T cells (OR 0.26, 0.1 – 0.5) yet increasing T-cell abundance is associated with decreased survival time in high-grade samples (HR 3.7, 1.4 – 10.1). Additionally, there are increased macrophage and decreased microglia signatures among high-grade samples and the C4 and C5 subtypes. It is hypothesized that expression of inhibitory immunomodulators contributes to a pro-tumorigenic microenvironment and represent potential therapeutic targets. In lieu of normal tissue in the data set, differential gene expression experiments between disease states reveals upregulated immunomodulators. Conventional immunomodulators, e.g. PDL1 and CTLA4, are expressed in low-grade samples with C3 subtype, which is abundant in craniopharyngioma. Alternative inhibitory immunomodulators, e.g. KDM1A, EZH2, CD276, are significantly expressed in high-grade samples including diffuse midline glioma. Overall, our analysis contributes to the understanding of the immune microenvironment and identifies potential mechanisms of immune escape among pediatric CNS tumors.
OTME-12. Role of the transsulfuration pathway in glioblastoma invasion
Authors: Garcia Joseph H , Jain Saket , Akins Erin A , Spatz Jordan M , Beniwal Angad S , Gill Sabraj A , Wolfe Kayla J , Cha Junghwa , Cha Junghwa , Kumar Sanjay , Aghi Manish K
Published: July 2021

Glioblastoma (GBM) is a primary malignant brain tumor with a median survival under two years. The poor prognosis GBM caries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Numerous factors have been proposed as the primary driving forces behind GBM’s ability to invade adjacent tissues rapidly, including alterations in the tumor’s cellular metabolism. Though studies have investigated links between GBM’s metabolic profile and its invasive capability, these studies have had two notable limitations. First, while infiltrating GBM cells extending beyond the tumor edge utilize adaptive cellular machinery to overcome stressors in their microenvironment, these cells at the invasive front have not been the ones sampled in invasive studies, which have used cell lines or banked tumor tissue taken from the readily accessible tumor core. Second, studies of invasion have primarily used two-dimensional (2D) culture systems, which fail to capture the dimensionality, mechanics, and heterogeneity of GBM invasion. To address these limitations, our team has developed two parallel approaches: acquisition of site-directed biopsies from patient GBMs to define regional heterogeneity in invasiveness, and engineering of 3D platforms to study invasion in vitro. Through utilization of these platforms, and by taking advantage of the system-wide, unbiased screens of metabolite profile and gene expression available, our team looks to identify targetable metabolic factors which drive cellular invasion in GBM. Untargeted metabolomics revealed cystathionine to be selectively enriched in the invasive tumor front of both site directed biopsies (fold change 5.8), and 3D organoid models (fold change 14.2). RNA sequencing revealed 7/30(23%) metabolic genes upregulated in the invasive tumor front were involved in cysteine or glutathione metabolism. These results highlight a clear role of the transsulfuration pathway in GBM invasion that our team looks to investigate with further targeted assays.
OTME-22. Bioinformatic evaluation of ECM molecules and angiogenic associate genes in diffuse midline glioma (DMG): mapping the tumour microenvironment
Authors: Kozhushko Nikita , Jedrysik Malwina , Fillmore Helen
Published: July 2021

Paediatric Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating cancer of an extremely aggressive nature, located in the pontine area of the brain. DIPG primarily affects children, with the average age of diagnosis between 6 and 7 years. Unfortunately, the outlook and overall survival remains bleak. While there has been impressive progress in identifying genes that are central to and drive DIPG growth; there remains several gaps in documenting the DIPG microenvironment landscape. The focus of this study is to begin to examine mRNA expression of genes associated with blood vessel development, angiogenesis, and extracellular matrix molecules (ECM) in normal brain development and DIPG by utilizing publicly available genomic datasets. In-depth bioinformatics from GSE26576 dataset included differential expression and gene ontology (GO) with KEGG pathway analyses using Gene Expression Omnibus (GEO) and DAVID, which have revealed a number of significantly upregulated genes that may affect DIPG angiogenic processes (p<0.05). 38 of such genes from 9 different GO terms were then included in a protein-to-protein interaction network that revealed a surprising connection between MMP16, CSPG4 and COL11A1. Subsequently, using R2 genomic visualisation platform from publicly available single cell RNAseq data we showcased the difference in their individual expression based on the molecular subtypes of DIPG histone 3 (H3) mutation (K27M, wild type and G34R) with a strong statistical significance (p<0.05). Interestingly, during normal paediatric development such genes showed consistent expression, suggesting their potential complications in DIPG angiogenesis. Overall, this bioinformatic approach has led to the identification of a set of interacting genes that will inform our in vitro and in vivo studies. This information will add to the documentation of the host/tumour microenvironment landscape and our plan is to continue to explore this area to map the spatial and temporal expression of these genes.
Privacy-preserving computation in the post-quantum era
Authors: Yu Yu , Xie Xiang
Published: July 2021

This perspectives article surveys the most promising privacy-preserving cryptographic technologies including secure multiparty computation, zero-knowledge proofs and fully homomorphic encryption, and their various real-world applications.
Cost-Effectiveness of Amphotericin B Deoxycholate Versus Itraconazole for Induction Therapy of Talaromycosis in Human Immunodeficiency Virus–Infected Adults in Vietnam
Authors: Buchanan James , Altunkaya James , Van Kinh Nguyen , Van Vinh Chau Nguyen , Trieu Ly Vo , Thi Thanh Thuy Pham , Hai Vinh Vu , Thi Hong Hanh Doan , Thuy Hang Nguyen , Phuong Thuy Tran , van Doorn Rogier , Thwaites Guy , Gray Alastair , Le Thuy
Published: July 2021

Background

Talaromycosis (penicilliosis) is an invasive fungal infection and a major cause of human immunodeficiency virus (HIV)–related deaths in Southeast Asia. Guidelines recommend induction therapy with amphotericin B deoxycholate; however, treatment with itraconazole has fewer toxic effects, is easier to administer, and is less expensive. Our recent randomized controlled trial in Vietnam found that amphotericin B was superior to itraconazole with respect to 6-month mortality. We undertook an economic evaluation alongside this trial to determine whether the more effective treatment is cost-effective.

Methods

Resource use, direct and indirect costs, and health and quality-of-life outcomes (measured using quality-adjusted life-years [QALYs]) were evaluated for 405 trial participants from 2012 to 2016. Both a Vietnamese health service and a broader societal costing perspective were considered. Mean costs and QALYs were combined to calculate the within-trial cost-effectiveness of amphotericin vs itraconazole from both perspectives.

Results

From a Vietnamese health service perspective, amphotericin increases costs but improves health outcomes compared to itraconazole, at a cost of $3013/QALY gained. The probability that amphotericin is cost-effective at a conventional (World Health Organization CHOICE) threshold of value for money is 46%. From a societal perspective, amphotericin is cost-reducing and improves outcomes compared to itraconazole, and is likely to be a cost-effective strategy at any value for money threshold greater than $0.

Conclusions

Our analysis indicates that induction therapy with amphotericin is a cost-effective treatment strategy for HIV-infected adults diagnosed with talaromycosis in Vietnam. These results provide the evidence base for health care providers and policy makers to improve access to and use of amphotericin.
Autism and the Right to a Hypersensitivity-Friendly Workspace
Authors: de Vries Bouke
Published: July 2021

Many individuals on the autism spectrum are hypersensitive to certain sensory stimuli. For this group, as well as for non-autistic individuals with sensory processing disorders, being exposed to e.g. fluorescent lights, perfume odours, and various sounds and noises can be real torment. In this article, I consider the normative implications of such offence for the design of office spaces, which is a topic that has not received any attention from philosophers. After identifying different ways in which the senses of hypersensitive workers might be protected within these spaces, I show that many of such accommodations can be made at reasonable cost, before arguing that doing so ought to be a legal requirement.
‘Take the Pill, It Is Only Fair’! Contributory Fairness as an Answer to Rose’s Prevention Paradox
Authors: Zameska Jay A
Published: July 2021

One proposal to significantly reduce cardiovascular disease is the idea of administering a ‘polypill’—a combination of drugs that reduce the risk of heart disease and carry few side effects—to everyone over the age of 55. Despite their promise, population strategies like the polypill have not been well-accepted. In this article, I defend the polypill (and consequently, other similar population strategies) by appealing to fairness. The argument focuses on the need to fairly distribute the costs to individuals. While the fact that population strategies like the polypill impose minor costs on everyone has primarily been used to criticize such strategies, I argue that it gives us a reason to support them. I argue that implementing a population strategy with the polypill contributes to the public good of ‘health system capacity’. I then explain that public goods have widely accepted obligations: they carry an obligation to fairly distribute the costs of the goods and prevent free-riding. Thus, we have at least one pro tanto moral reason to implement the polypill. As such, this article challenges the current literature on the topic, which has largely held adopting population strategies like the polypill to be unjustifiable.
Development of convolutional neural networks for an electron-tracking Compton camera
Authors: Ikeda Tomonori , Takada Atsushi , Abe Mitsuru , Yoshikawa Kei , Tsuda Masaya , Ogio Shingo , Sonoda Shinya , Mizumura Yoshitaka , Yoshida Yura , Tanimori Toru
Published: July 2021

The Electron-Tracking Compton Camera (ETCC), which is a complete Compton camera that tracks Compton scattering electrons with a gas micro time projection chamber, is expected to open up MeV gamma-ray astronomy. The technical challenge for achieving several degrees of the point-spread function is precise determination of the electron recoil direction and the scattering position from track images. We attempted to reconstruct these parameters using convolutional neural networks. Two network models were designed to predict the recoil direction and the scattering position. These models marked 41$^\circ$ of angular resolution and 2.1 mm of position resolution for 75 keV electron simulation data in argon-based gas at 2 atm pressure. In addition, the point-spread function of the ETCC was improved to 15$^\circ$ from 22$^\circ$ for experimental data from a 662 keV gamma-ray source. The performance greatly surpassed that using traditional analysis.
National Blockchain Laws as a Threat to Capital Markets Integration
Authors: Lehmann Matthias
Published: July 2021

Various states have started providing private law frameworks for blockchain transfers and crypto assets. France and Liechtenstein have adopted the first acts, while a commission of the British government sees no difficulties in extending property protection under the common law to crypto assets. In the USA, an amendment to the Uniform Commercial Code has been suggested, which has not stopped some states going their own, different way. The aim in all cases is to promote the use of modern distributed ledger technology and enhance investor protection. While these initiatives will increase legal certainty, they differ significantly. This has an important downside: there is a strong risk that the blockchain will be made subject to diverging legal rules. Similar to the world of intermediated securities, various national laws will need to be consulted to determine the rights and privileges of investors. This may increase transaction costs, thwart interoperability, and produce thorny conflict-of-laws problems. Markets risk being fragmented into national segments, with an inevitable diminution of their depth and liquidity. As a remedy, this article suggests developing uniform rules for the blockchain. Before national legislators and judges once again divide the world through idiosyncratic rules, the private law of crypto assets should be harmonized to the highest degree possible. Uniform rules should ideally be forged at the global level, by fora like the International Institute for the Unification of Private Law (Unidroit), the United Nations Commission on International Trade Law (UNCITRAL), and the Hague Conference on Private International Law. In the absence of worldwide rules, uniformization of private law should take place at the regional level—for instance, by the European Union. The article makes specific suggestions as to how this can be achieved and what the content of those rules should be.
Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool
Authors: O’Toole Áine , Scher Emily , Underwood Anthony , Jackson Ben , Hill Verity , McCrone John T , Colquhoun Rachel , Ruis Chris , Abu-Dahab Khalil , Taylor Ben , Yeats Corin , du Plessis Louis , Maloney Daniel , Medd Nathan , Attwood Stephen W , Aanensen David M , Holmes Edward C , Pybus Oliver G , Rambaut Andrew
Published: July 2021

The response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the ‘real-time’ generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic’s transmission lineages.
Noble gases and neuroprotection: summary of current evidence
Authors: Höllig Anke , Coburn Mark
Published: July 2021

Purpose of review

To summarize the current data on neuroprotection derived by noble gas treatment focusing on xenon and argon.

Recent findings

Both xenon and argon have demonstrated neuroprotective properties in an array of disease models. However, current data for argon after traumatic brain injury (TBI) is conflicting. Recent human data is only available for xenon showing some beneficial aspects (fewer adverse events) but no effect on outcomes, such as incidence of postoperative delirium.

Promising results are available for neuroprotection derived by noble gas treatment. Results for xenon are more consistent than those for argon. The mechanism of action of xenon (noncompetitive NMDA-receptor inhibition) is also better understood compared with that of argon. The evidence for argon's neuroprotective actions (particularly after TBI) remains uncertain.
Five-Year Longitudinal Cohort Study Determines the Critical Intervals for Periodic Audiometric Testing Based on 5070 Tests of Metallurgical Workers Exposed and Nonexposed to Noise
Authors: Silva Vagner Antonio Rodrigues , Guimarães Alexandre Caixeta , Lavinsky Joel , Pauna Henrique Furlan , Duarte Alexandre Scalli Mathias , Castilho Arthur Menino , Chone Carlos Takahiro , Crespo Agrício Nubiato
Published: July 2021

Objectives:

To compare the progression of 3-, 4-, and 6-kHz thresholds (pure-tone average) over 5 years and determine the most critical period for occupational risk among workers exposed and nonexposed to noise.

Design:

Metallurgical workers were divided into 2 groups: noise-exposed and non–noise-exposed groups. The 6 initial audiometric tests of each worker were analyzed as baseline test and annual tests 1 to 5.

Results:

A total of 845 workers were included, 748 in the noise-exposed group and 97 in the non–noise-exposed group, resulting in 5070 tests analyzed. The nonexposed group showed no significant difference in the mean pure-tone averages between any of the annual tests in either ear. In the exposed group, a significant difference was observed in mean pure-tone averages between baseline and Test1 (p = 0.001 right ear; p = 0.001 left ear), between Test3 and Test4 (p = 0.002 right ear; p = 0.005 left ear), and between Test4 and Test5 (p = 0.003 right ear; p = 0.001 left ear). There was no difference between Test1 and Test2 or between Test2 and Test3 in either ear.

Conclusions:

The progression of pure-tone averages at 3, 4, and 6 kHz differed between workers exposed and nonexposed to noise. Noise-exposed workers had a significant progressive worsening of audiometric thresholds after 3 years of employment. This study identified, in an unprecedented way, two critical periods of noise exposure: in the first year and after the third year of employment in a noisy environment.
Oral Is as Effective as Intravenous Tranexamic Acid at Reducing Blood Loss in Thoracolumbar Spinal Fusions
Authors: Yu Charles C. , Fidai Mohsin , Washington Travis , Bartol Stephen , Graziano Gregory
Published: July 2021

Study Design.

A prospective randomized trial at a university affiliated tertiary medical center between February 2017 and March 2020.

Objective.

The aim of this study was to compare perioperative blood loss in patients undergoing elective posterior thoracolumbar fusion who were treated with IV versus PO TXA.

Summary of Background Data.

The use of antifibrinolytic agents such as tranexamic acid (TXA) to decrease operative blood loss and allogenic blood transfusions is well documented in the literature. Although evidence supports the use of intravenous (IV) and topical formulations of TXA in spine surgery, the use of oral (PO) TXA has not been studied.

Methods.

A total of 261 patients undergoing thoracolumbar fusion were randomized to receive 1.95 g of PO TXA 2 hours preoperatively or 2 g IV TXA (1 g before incision and 1 g before wound closure) intraoperatively. The sample was further stratified into three categories based on number of levels fused (one-to two-level fusions, three to five, and more than five). The primary outcome was the reduction of hemoglobin. Secondary outcomes included calculated blood loss, drain output, postoperative transfusion, complications, and length of hospital stay. Equivalence analysis was performed with a two one-sided test.

Results.

One hundred thirty-seven patients received IV and 124 received PO TXA. The average age was 62 ± 13 years (mean ± SD), including 141 females and 120 males. Revision cases comprised of 67% of the total sample. Patient demographic factors were similar between groups except for weight, BMI, and preoperative platelet count. The mean reduction of hemoglobin was similar between IV and PO groups (3.56 vs. 3.28 g/dL, respectively; P = 0.002, equivalence). IV TXA group had a higher transfusion rate compared to PO TXA group (22 patients [19%] vs. 12 patients [10%]; P = 0.03). In addition, IV group had longer length of stay (LOS) than PO group (4.4 vs. 3.7 days; P = 0.02).

Conclusion.

Patients treated with IV and PO TXA experienced the same perioperative blood loss after small and large spinal fusions. In subgroup analysis, the intermediate (three to five level) spinal fusions had less blood loss with PO TXA than IV TXA. Given its lower cost, PO TXA represents a superior alternative to IV TXA in patients undergoing elective posterior thoracolumbar fusion and may improve health care cost-efficiency in the studied population.

Level of Evidence: 1
An Objective Assessment of Lumbar Spine Degeneration/Ageing Seen on MRI Using An Ensemble Method—A Novel Approach to Lumbar MRI Reporting
Authors: Sneath Robert J.S. , Khan Atif , Hutchinson Charles
Published: July 2021

Study Design.

Retrospective, randomized, radiographic study assessing age-related changes (ARCs) on lumbar magnetic resonance imaging (MRI) using an ensemble method.

Objectives.

This study proposed to develop a novel reporting method to calculate a predicted “age estimate” for the ARC seen on lumbar MRI.

Summary of Background Data.

Lumbar MRI reports include pathological findings but usually not the prevalence data of common findings which has been shown to decrease the need for narcotics in the management of non-specific lower back pain (NSLBP). Comparing the normal age estimation for lumbar spine degenerative changes/ARC on MRI and comparing this to the patient's real age may improve patient outcome in the management of NSLBP.

Methods.

A total of 60 lumbar MRI were taken from patients aged between 0 and 100 years. Lumbar MRI features reported as associated with age on review of the literature were measured on each MRI and statistically evaluated for correlation with age. Factors found to be associated were then entered into an ensemble model consisting of several machine learning techniques. The resulting ensemble model was then tested to predict age for a further 10 random lumbar MRI scans. One further lumbar MRI was then assessed for observer variability.

Results.

Features that correlated with age were disc signal intensity, the appearance of paravertebral and psoas muscle, disc height, facet joint size, ligamentum flavum thickness, Schmorl nodes, Modic changes, vertebral osteophytes, and high-intensity zones. With the ensemble model, 80% of estimated spinal age were within 11 years of the subjects’ physical age.

Conclusion.

It would appear that the intervertebral discs, and many other structures that are subjected to loading in and around the lumbar spine change their lumbar MRI appearance in a predictable way with increasing age. ARC on lumbar MRI can be assessed to predict an “expected age” for the subject.

Level of Evidence: 2
Combining Expandable Interbody Cage Technology With a Minimally Invasive Technique to Harvest Iliac Crest Autograft Bone to Optimize Fusion Outcomes in Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery
Authors: Virk Sohrab , Vaishnav Avani S. , Sheha Evan , Urakawa Hikari , Sato Kosuke , Othman Yahya , Chaudhary Chirag , Lee Ryan , Cong Guang-Ting , Chaudhary Saad , Qureshi Sheeraz A.
Published: July 2021

Study Design:

This was a retrospective cohort review.

Objective:

The objective of this study was to determine the rate of fusion associated with an expandable cage and iliac crest bone graft in minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) surgery.

Summary of Background Data:

MI-TLIF is a commonly performed procedure, but challenges inherent in MI-TLIF technique can make achieving an interbody fusion difficult.

Methods:

A retrospective review was performed on consecutive patients treated with an MI-TLIF for degenerative lumbar pathology. Patients that completed patient-reported outcome measures and 1-year computed tomography (CT)-scans for fusion analysis were included. Fusion morphology was analyzed by evaluating CT scans for location of bridging trabecular bone in relation to the cage. Patients with bridging bone were considered fused. Preoperative and postoperative health-related quality of life scores were compared. A Kolmogrov-Smirnoff test was used to determine normality of health-related outcome scores. A Friedman 2-way analysis of variance by ranks with pairwise comparisons to determine statistical significance of differences between the date of a follow-up examination and preoperative examination was done.

Results:

Of 75 patients evaluated 23 patients were excluded due to loss to follow-up, adjacent segment degeneration, inability to obtain a CT scan, or reoperation for nonfusion related symptoms. Of 61 disk spaces that were included, 55 had bridging bone through the intervertebral cage, resulting in an overall fusion rate of 90.2%. There was a higher rate of fusion at L5−S1 as compared to L4−L5. There was mean improvement in patient-reported outcome measures for Oswestry Disability Index, Short Form-12 Physical Component Score, Visual Analog Scale Back/Leg pain, and Patient-Reported Outcome Measurement Information System Physical Function. There were no complications associated with iliac crest bone graft harvesting.

Conclusion:

Combining an expandable cage with iliac crest autograft bone harvested through a minimally invasive technique can allow for improved fusion rates without graft-site complications in MI-TLIF surgery.
Regionalization of Critical Care in the United States: Current State and Proposed Framework From the Academic Leaders in Critical Care Medicine Task Force of the Society of Critical Care Medicine*
Authors: Leung Sharon , Pastores Stephen M. , Oropello John M. , Lilly Craig M. , Galvagno Samuel M. , Badjatia Neeraj , Jacobi Judith , Herr Daniel L. , Oliveira Jason David ,   for the Academic Leaders in Critical Care Medicine Task Force of the Society of Critical Care Medicine
Published: July 2021

Objectives:

The Society of Critical Care Medicine convened its Academic Leaders in Critical Care Medicine taskforce on February 22, 2016, during the 45th Critical Care Congress to develop a series of consensus papers with toolkits for advancing critical care organizations in North America. The goal of this article is to propose a framework based on the expert opinions of critical care organization leaders and their responses to a survey, for current and future critical care organizations, and their leadership in the health system to design and implement successful regionalization for critical care in their regions.

Data Sources and Study Selection:

Members of the workgroup convened monthly via teleconference with the following objectives: to 1) develop and analyze a regionalization survey tool for 23 identified critical care organizations in the United States, 2) assemble relevant medical literature accessed using Medline search, 3) use a consensus of expert opinions to propose the framework, and 4) create groups to write the subsections and assemble the final product.

Data Extraction and Synthesis:

The most prevalent challenges for regionalization in critical care organizations remain a lack of a strong central authority to regulate and manage the system as well as a lack of necessary infrastructure, as described more than a decade ago. We provide a framework and outline a nontechnical approach that the health system and their critical care medicine leadership can adopt after considering their own structure, complexity, business operations, culture, and the relationships among their individual hospitals. Transforming the current state of regionalization into a coordinated, accountable system requires a critical assessment of administrative and clinical challenges and barriers. Systems thinking, business planning and control, and essential infrastructure development are critical for assisting critical care organizations.

Conclusions:

Under the value-based paradigm, the goals are operational efficiency and patient outcomes. Health systems that can align strategy and operations to assist the referral hospitals with implementing regionalization will be better positioned to regionalize critical care effectively.
Factors Associated With Prolonged Mechanical Ventilation in Patients With Subarachnoid Hemorrhage—The RAISE Score*
Authors: Rass Verena , Ianosi Bogdan-Andrei , Lindlbauer Moritz , Lindner Anna , Kofler Mario , Schiefecker Alois J. , Pfausler Bettina , Beer Ronny , Helbok Raimund
Published: July 2021

OBJECTIVES:

Patients suffering from spontaneous subarachnoid hemorrhage frequently require mechanical ventilation. Here, we aimed to identify factors associated with prolonged mechanical ventilation in subarachnoid hemorrhage patients and to create a new predictive score for prolonged mechanical ventilation.

DESIGN:

Prospective cohort study with retrospective data analysis.

SETTING:

Neurocritical care unit at a tertiary academic medical center.

PATIENTS:

Two hundred ninety-seven consecutive nontraumatic adult subarachnoid hemorrhage patients.

METHODS:

In patients with mechanical ventilation, we identified factors associated with mechanical ventilation greater than 48 hours, greater than 7 days, and greater than 14 days compared with mechanical ventilation less than or equal to 48 hours, less than or equal to 7 days, or less than or equal to 14 days in multivariable generalized linear models. Ventilated patients who died before 48 hours, 7 days, or 14 days and those never ventilated were excluded from the respective analysis. We incorporated those factors into a new prognostic score (the RAISE score) to predict prolonged mechanical ventilation greater than 7 days. The calculation was based on a random dataset of 60% of subarachnoid hemorrhage patients and was internally validated.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Patients were 57 years old (interquartile range, 47–68 yr) and presented with a median Hunt and Hess grade of 3 (1–5). Two hundred forty-two patients (82%) required mechanical ventilation for 9 days (2–20 d). In multivariable analysis, a higher Acute Physiology Score was associated with mechanical ventilation greater than 48 hours, greater than 7 days, and greater than 14 days, a higher Hunt and Hess grade with greater than 7 days and greater than 14 days. Early neuroimaging findings were associated with mechanical ventilation greater than 48 hours (hydrocephalus; high-grade Subarachnoid Hemorrhage Early Brain Edema Score), greater than 7 days (high-grade Subarachnoid Hemorrhage Early Brain Edema Score, co-occurrence of intracerebral bleeding) but not with prolonged mechanical ventilation greater than 14 days. The RAISE score, including age, Acute Physiology Score, Hunt and Hess grade, Subarachnoid Hemorrhage Early Brain Edema Score, and the co-occurrence of intracerebral hemorrhage accurately stratified patients by prolonged mechanical ventilation greater than 7 days (C-statistic 0.932). A RAISE score of 12 predicted 60% likelihood of mechanical ventilation greater than 7 days.

CONCLUSIONS:

Initial disease severity and neuroimaging findings detected within 24 hours after ICU admission were associated with the need for prolonged mechanical ventilation in patients with subarachnoid hemorrhage. These results may be helpful for patient families and caregivers to better anticipate the course of therapy.
Mobile health in preventive cardiology: current status and future perspective
Authors: Kozik Michael , Isakadze Nino , Martin Seth S.
Published: July 2021

Purpose of review

Despite cutting edge acute interventions and growing preventive strategies supported by robust clinical trials, cardiovascular disease (CVD) has stubbornly persisted as a leading cause of death in the United States and globally. The American Heart Association recognizes mobile health technologies (mHealth) as an emerging strategy in the mitigation of CVD risk factors, with significant potential for improving population health. The purpose of this review is to highlight and summarize the latest available literature on mHealth applications and provide perspective on future directions and barriers to implementation.

Recent findings

While available randomized controlled trials and systematic reviews tend to support efficacy of mHealth, published literature includes heterogenous approaches to similar problems with inconsistent results. Some of the strongest recent evidence has been focused on the use of wearables in arrhythmia detection. Systematic reviews of mHealth approaches demonstrate benefit when applied to risk factor modification in diabetes, cigarette smoking cessation, and physical activity/weight loss, while also showing promise in multi risk factor modification via cardiac rehabilitation.

Evidence supports efficacy of mHealth in a variety of applications for CVD prevention and management, but continued work is needed for further validation and scaling. Future directions will focus on platform optimization, data and sensor consolidation, and clinical workflow integration. Barriers include application heterogeneity, lack of reimbursement structures, and inequitable access to technology. Policies to promote access to technology will be critical to evidence-based mHealth technologies reaching diverse populations and advancing health equity.
Subtype-specific trends in the clinical picture of primary aldosteronism over a 13-year period
Authors: Saito Kohei , Kurihara Isao , Itoh Hiroshi , Ichijo Takamasa , Katabami Takuyuki , Tsuiki Mika , Wada Norio , Yoneda Takashi , Sone Masakatsu , Oki Kenji , Yamada Tetsuya , Kobayashi Hiroki , Tamura Kouichi , Ogawa Yoshihiro , Kawashima Junji , Inagaki Nobuya , Yamamoto Koichi , Yamada Masanobu , Kamemura Kohei , Fujii Yuichi , Suzuki Tomoko , Yasoda Akihiro , Tanabe Akiyo , Naruse Mitsuhide
Published: July 2021

Objective:

Primary aldosteronism has two main clinically and biologically distinct subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). We aimed to evaluate the changes of each subtype's clinical characteristics over a 13-year period.

Methods:

This retrospective study involved time-trend analyses to identify changes in the clinical features of APA and BAH at diagnosis (2006–2018). A nationwide database from 41 Japanese referral centers was searched, which identified 2804 primary aldosteronism patients with complete baseline information and adrenal venous sampling (AVS) data.

Results:

The proportion of patients with APA decreased from 51% in 2006–2009 to 22% in 2016–2018. Among the 1634 patients with BAH, trend analyses revealed decreases in hypertension duration (median 7--3 years; P < 0.01) and hypokalemia prevalence (18--11%; P < 0.01). However, among the 952 patients with APA, there were no significant changes in hypertension duration (median 8 years) and hypokalemia prevalence (overall 70%). Furthermore, the APA group had a trend towards increased use of multiple hypertensive drugs at diagnosis (30--43%; P < 0.01). When subtypes were reclassified according to the precosyntropin stimulation AVS data, APA patients tended to be diagnosed earlier and at milder forms, consistent with the trend in overall primary aldosteronism patients.

Conclusion:

During 2006–2018, we identified marked subtype-specific trends in the clinical findings at the diagnosis of primary aldosteronism. Our results suggested that the emphasis on the implementing cosyntropin stimulation during AVS might lead to under-identification of APA, especially in patients with mild or early cases.
Meibomian Gland Dysfunction and Lipid Profile: A Study Among Pregnant Women
Authors: Kyei Samuel , Asiedu Kofi , Ephraim Richard K.D. , Animful Stephen , Adanusa Madison , Ali-Baya Stephen Karim , Akorsah Belinda , Sekyere Mabel Antwiwaa
Published: July 2021

Purpose:

This study aimed to estimate the frequency of meibomian gland dysfunction (MGD) and its associated factors among pregnant women.

Methods:

This was a hospital-based cross-sectional study of consecutive pregnant women visiting the University of Cape Coast hospital's antenatal clinic. Meibomian gland assessment and tear function test were performed along with the administration of a symptom questionnaire. Correlation, analysis of variance, and logistic regression analyses were used to examine predictors of MGD.

Results:

All 201 pregnant women who met the inclusion criteria and gave informed consent were included in the study. The mean age of the entire sample was 29.96 (±4.74) years. The frequency of MGD among the cohort of pregnant women was 22.9% (95% confidence interval, 17.4%–28.9%). Univariate logistic regression revealed that the following factors were significantly associated with MGD: high-density lipoprotein (HDL) (odds ratio [OR] 1.017; 95% confidence interval [CI], 1.001–1.034; P=0.042), total cholesterol (TC) (OR 1.009; 95% CI, 1.003–1.016; P=0.006), and low-density lipoprotein (LDL) (OR 1.008; 95% CI, 1.00–1.016; P=0.049). In multivariate analysis, the model confirmed that MGD was not significantly associated with TC, LDL, and HDL.

Conclusions:

In summary, this study showed a high frequency of MGD in pregnant women but comparable with that reported in the normal population. Clinicians examining pregnant women for dry eye disease may need to pay attention to other causative instigators aside MGD to enable the clinicians to make an appropriate etiology-based diagnosis.
Novel Bacterial Cellulose Membrane to Reduce Fibrosis Following Trabeculectomy
Authors: Yazgan Serpil , Tekin Ishak Ozel , Akpolat Nusret , Koc Ozhan
Published: July 2021

Purpose:

The aim was to evaluate the effectiveness of bacterial cellulose membrane (BCM) in preventing fibrosis in trabeculectomy and the biocompatibility of BCM with conjunctiva and sclera.

Materials and Methods:

Twenty-one eyes of 21 adult rabbits underwent fornix-based trabeculectomy. Standard surgery was done to control group (CG, n=7). Mitomycin-C (MMC) (0.3 mg/mL, 3 min) was applied to MMC group only (MMCG, n=7). BCM (~100 µm thick, 10×10 mm, single layer) was covered on the sclerotomy area before conjunctiva was closed in BCM group (BCMG, n=7). Intraocular pressures (IOP) were measured before, and 7, 14, 28, and 45 days after surgery (IOP-POD7, POD14, POD28, POD45). The IOP decrease were expressed as DIOP%-POD7, DIOP%-POD14, DIOP%-POD28, and DIOP%-POD45. The rabbits were sacrificed on the 45th day. Conjunctival vessel number, degrees of fibrosis, total inflammation, foreign body reaction, inflammatory cell types (B cells, T cells, plasma cells), macrophages, bleb spaces and the expression of α-smooth muscle actin were studied using histopathology and immunohistochemistry techniques. The groups were compared using nonparametric tests.

Results:

There was no statistically significant difference between the groups regarding baseline IOP and DIOP%-POD7 (P>0.05). While DIOP%-POD14, 28 and 45 were similar between BCMG and MMCG, they were significantly lower in CG (P<0.05). The lowest conjunctival vessel number was detected in the MMCG but the difference was not significant. There was no difference between BCMG and CG with regard to the numbers of B cells, T cells, and macrophages, however, these cells were significantly lower in MMCG (P<0.05). Five cases had mild and 2 cases had moderate foreign body reaction in the BCMG. There was mild to moderate inflammation in all BCM cases. While fibrosis and α-smooth muscle actin staining were higher in the CG (P<0.001), they were minimal in the BCM and MMCGs.

Conclusions:

BCM showed good biocompatibility and provided better control of IOP with minimal fibrosis at the trabeculectomy site compared with the control group.