Glyburide is Associated with Attenuated Vasogenic Edema in Stroke Patients

Background

Brain edema is a serious complication of ischemic stroke that can lead to secondary neurological deterioration and death. Glyburide is reported to prevent brain swelling in preclinical rodent models of ischemic stroke through inhibition of a non-selective channel composed of sulfonylurea receptor 1 and transient receptor potential cation channel subfamily M member 4. However, the relevance of this pathway to the development of cerebral edema in stroke patients is not known.

Methods

Using a case–control design, we retrospectively assessed neuroimaging and blood markers of cytotoxic and vasogenic edema in subjects who were enrolled in the glyburide advantage in malignant edema and stroke-pilot (GAMES-Pilot) trial. We compared serial brain magnetic resonance images (MRIs) to a cohort with similar large volume infarctions. We also compared matrix metalloproteinase-9 (MMP-9) plasma level in large hemispheric stroke.

Results

We report that IV glyburide was associated with T2 fluid-attenuated inversion recovery signal intensity ratio on brain MRI, diminished the lesional water diffusivity between days 1 and 2 (pseudo-normalization), and reduced blood MMP-9 level.

Conclusions

Several surrogate markers of vasogenic edema appear to be reduced in the setting of IV glyburide treatment in human stroke. Verification of these potential imaging and blood biomarkers is warranted in the context of a randomized, placebo-controlled trial.     

MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma

Glioblastomas (GBMs) diffusely infiltrate the brain, making complete removal by surgical resection impossible. The mixture of neoplastic and nonneoplastic cells that remain after surgery form the biological context for adjuvant therapeutic intervention and recurrence. We performed RNA-sequencing (RNA-seq) and histological analysis on radiographically guided biopsies taken from different regions of GBM and showed that the tissue contained within the contrast-enhancing (CE) core of tumors have different cellular and molecular compositions compared with tissue from the nonenhancing (NE) margins of tumors. Comparisons with the The Cancer Genome Atlas dataset showed that the samples from CE regions resembled the proneural, classical, or mesenchymal subtypes of GBM, whereas the samples from the NE regions predominantly resembled the neural subtype. Computational deconvolution of the RNA-seq data revealed that contributions from nonneoplastic brain cells significantly influence the expression pattern in the NE samples. Gene ontology analysis showed that the cell type-specific expression patterns were functionally distinct and highly enriched in genes associated with the corresponding cell phenotypes. Comparing the RNA-seq data from the GBM samples to that of nonneoplastic brain revealed that the differentially expressed genes are distributed across multiple cell types. Notably, the patterns of cell type-specific alterations varied between the different GBM subtypes: the NE regions of proneural tumors were enriched in oligodendrocyte progenitor genes, whereas the NE regions of mesenchymal GBM were enriched in astrocytic and microglial genes. These subtype-specific patterns provide new insights into molecular and cellular composition of the infiltrative margins of GBM.Glioma cells diffusely infiltrate the brain and intermingle with neural cells in the surrounding brain tissue, resulting in a complex mixture that includes variable proportions of glioma cells, neurons, and various lineages of reactive or recruited glia. At the infiltrative margins of glioblastoma (GBM), the nonneoplastic brain cells can far outnumber the glioma cells and, therefore, will have a significant effect on the molecular features of the tissue. Expression profiling and whole genome sequencing from hundreds of GBM specimens by The Cancer Genome Atlas (TCGA) has revealed a broad spectrum of genetic alterations and discrete expression signatures or subtypes that stratify the majority of patients (1, 2). These studies analyzed tumor samples that were removed during surgery, but were not radiographically localized and, therefore, do not address the question of how the molecular signature may vary across different regions of a tumor. Recent studies have sampled multiple regions within a GBM and shown that more than one molecular subtype can coexist within a single tumor (3). However, the effect of varying cellular composition on GBM subtype, particularly the contribution of nonneoplastic cells, has not been addressed.GBM typically appears as a contrast-enhancing mass, which represents the highly cellular core of the tumor with vascular proliferation and blood–brain barrier breakdown. This contrast-enhancing (CE) region is typically surrounded by a diffuse, nonenhancing (NE) region of abnormal T2/FLAIR signal, which represents edematous brain tissue with varying numbers of infiltrating glioma cells. The primary treatment of GBM is surgical resection, during which the surgeon removes as much of the CE mass as possible. Thus, molecular and genetic profiling of GBM, including the TCGA effort, has predominantly used samples from the CE regions of tumor. However, it is the NE regions of glioma that are left behind after surgery, which neurooncologists must treat and which inevitably give rise to recurrence. Thus, there is immense prognostic and therapeutic significance to understanding the cellular and molecular features of the NE regions of tumor, yet often these areas are not resected and, therefore, have not been directly studied.There are two major obstacles to this goal. The first is the surgical challenge of radiographically localized sampling of the NE tumor margins. The second is the issue of the complex cellular composition that characterizes these regions of diffuse infiltration. In this study, we have addressed both challenges, and associated distinct molecular and cellular features of the NE regions of GBM with the molecular subtype, as defined by the resected CE regions of the tumor.     

Optimization of Novel Mucoadhesive In Situ Film Forming Periodontal Drug Delivery System for Chemotherapeutic Agents

Introduction

The objective of the present investigation was to develop and evaluate mucoadhesive in situ film forming periodontal drug delivery system (MIFPDDS) for local delivery of chemotherapeutic agents. Ethyl cellulose, a film forming release retardant, was used in combination with Eudragit RL100, a mucoadhesive polymer, and polyvinylpyrrolidone K-30 to develop MIFPDDS.

Materials and methods

A simplex lattice design was employed to achieve an optimum solvent blend (N-methyl-2-pyrrolidone, polyethylene glycol-200, and propylene glycol) which has rapid film formation capacity and low viscosity. The prepared MIFPDDS was evaluated for various parameters such as in vitro film forming capacity, viscosity, in vitro diffusion study, ex vivo mucoadhesion study, stability study, and compatibility. A 32 full-factorial design was used to investigate the influence of formulation variables.

Results and discussion

Drug release data from all formulations were fitted to different kinetic models, and the Korsmeyer–Peppas model was found the best fit model. Increasing the concentration of each polymeric component increases viscosity, and time for 50, 70, and 90 % drug release was observed and graphically represented by the surface response and contour plots. The formulation of batches MIF1—PCM4, MIF6, and MIF7 failed to give the desired results for the first hour drug release and MIF8 and MIF9 failed to show viscosity below 70 cPs.

Conclusion

The formulation of batch MIF5 containing 3 % (w/v) of ethyl cellulose and 8 % (w/v) of Eudragit RL100 was considered as optimum formulation.     

Sequencing‐based microsatellite instability testing using as few as six markers for high‐throughput clinical diagnostics

Microsatellite instability (MSI) testing of colorectal cancers (CRCs) is used to screen for Lynch syndrome (LS), a hereditary cancer‐predisposition, and can be used to predict response to immunotherapy. Here, we present a single‐molecule molecular inversion probe and sequencing‐based MSI assay and demonstrate its clinical validity according to existing guidelines. We amplified 24 microsatellites in multiplex and trained a classifier using 98 CRCs, which accommodates marker specific sensitivities to MSI. Sample classification achieved 100% concordance with the MSI Analysis System v1.2 (Promega) in three independent cohorts, totaling 220 CRCs. Backward–forward stepwise selection was used to identify a 6‐marker subset of equal accuracy to the 24‐marker panel. Assessment of assay detection limits showed that the 24‐marker panel is marginally more robust to sample variables than the 6‐marker subset, detecting as little as 3% high levels of MSI DNA in sample mixtures, and requiring a minimum of 10 template molecules to be sequenced per marker for >95% accuracy. BRAF c.1799 mutation analysis was also included to streamline LS testing, with all c.1799T>A variants being correctly identified. The assay, therefore, provides a cheap, robust, automatable, and scalable MSI test with internal quality controls, suitable for clinical cancer diagnostics.     

Patient Radiation Exposure in a Modern,Large-Volume,Pediatric Cardiac Catheterization Laboratory

Radiation exposure from pediatric cardiac catheterization may be substantial, although published estimates vary. We sought to report patient radiation dose across a range of diagnostic and interventional cases in a modern, high-volume pediatric catheterization laboratory. We retrospectively reviewed diagnostic and interventional cases performed in our pediatric catheterization laboratory from 1 April 2009 to 30 September 2011 for which radiation usage data were available as reported by the Artis Zee^® (Siemens Medical Solutions) system. Electrophysiology cases were excluded. Radiation dose was quantified as air kerma dose (mGy) and dose-area product (DAP; μGy m²). The DAP was converted to an effective dose millisievert (mSv) using the Monte Carlo method. Radiation usage data were available from 2,265 diagnostic and interventional cases with an overall median air kerma dose of 135 mGy [interquartile range (IQR) 59–433], median DAP of 760 μGy m² (IQR 281–2,810), of which 75 % (IQR 59–90 %) was derived from fluoroscopy, and median effective dose of 6.2 mSv (IQR 2.7–14.1). Air kerma dose from a single camera >2,000 mGy occurred in 1.8 % of cases. Significant differences in all measures of radiation exposure existed based on procedural and interventional types (p = 0.0001), with interventional cases associated with the highest effective dose after adjusting for patient weight category (p < 0.001). Patient weight, age, fluoroscopy time, and proportional use of digital acquisition were independent predictors of exposure (p ≤ 0.001; R ² = 0.59–0.64). In a modern, large-volume pediatric catheterization laboratory, the median effective dose is 6.2 mSv with a wide range of exposure based on patient- and procedure-specific factors. Radiation monitoring is an important component of a pediatric laboratory and further dose reduction strategies are warranted.     

The Biomedical Research Hub: a federated platform for patient research data

ObjectiveThe objective was to develop and operate a cloud-based federated system for managing, analyzing, and sharing patient data for research purposes, while allowing each resource sharing patient data to operate their component based upon their own governance rules. The federated system is called the Biomedical Research Hub (BRH).Materials and MethodsThe BRH is a cloud-based federated system built over a core set of software services called framework services. BRH framework services include authentication and authorization, services for generating and assessing findable, accessible, interoperable, and reusable (FAIR) data, and services for importing and exporting bulk clinical data. The BRH includes data resources providing data operated by different entities and workspaces that can access and analyze data from one or more of the data resources in the BRH.ResultsThe BRH contains multiple data commons that in aggregate provide access to over 6 PB of research data from over 400 000 research participants.Discussion and conclusionWith the growing acceptance of using public cloud computing platforms for biomedical research, and the growing use of opaque persistent digital identifiers for datasets, data objects, and other entities, there is now a foundation for systems that federate data from multiple independently operated data resources that expose FAIR application programming interfaces, each using a separate data model. Applications can be built that access data from one or more of the data resources.     

A Scoping Review on the Concept of Physician Caring

BackgroundPhysicians’ interest in the health and well-being of their patients is a tenet of medical practice. Physicians’ ability to act upon this interest by caring for and about their patients is central to high-quality clinical medicine and may affect burnout. To date, a strong theoretical and empirical understanding of physician caring does not exist. To establish a practical, evidence-based approach to improve health care delivery and potentially address physician burnout, we sought to identify and synthesize existing conceptual models, frameworks, and definitions of physician caring.MethodsWe performed a scoping review on physician caring. In November 2019 and September 2020, we searched PubMed MEDLINE, Embase, PsycINFO, CINAHL, and CENTRAL Register of Controlled Trials to identify conceptual models, frameworks, and definitions of physician caring. Eligible articles involved discussion or study of care or caring among medical practitioners. We created a content summary and performed thematic analysis of extracted data.ResultsOf 11,776 articles, we reviewed the full text of 297 articles; 61 articles met inclusion criteria. Commonly identified concepts referenced Peabody’s “secret of care” and the ethics of care. In bioethics, caring is described as a virtue. Contradictions exist among concepts of caring, such as whether caring is an attitude, emotion, or behavior, and the role of relationship development. Thematic analysis of all concepts and definitions identified six aspects of physician caring: (1) relational aspects, (2) technical aspects, (3) physician attitudes and characteristics, (4) agency, (5) reciprocity, and (6) physician self-care.DiscussionCaring is instrumental to clinical medicine. However, scientific understanding of what constitutes caring from physicians is limited by contradictions across concepts. A unifying concept of physician caring does not yet exist. This review proposes six aspects of physician caring which can be used to develop evidence-based approaches to improve health care delivery and potentially mitigate physician burnout.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-07382-4.KEY WORDS: caring, physician-patient relationships, burnout, wellness, purpose     

Original research: Widespread gaps in the quality of care for primary biliary cholangitis in UK

ObjectivePrimary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines.DesignData were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ² analysis for variation in performance between trusts.Results790 patients’ medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297).ConclusionOur findings identify a broad-based deficiency in ‘real-world’ PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.