Konnyaku jelly: A quick preparation and cost effective ultrasound-guided IV phantom model.

Clinicians commonly place ultrasound-guided intravenous catheters in peripheral veins for the diagnostic and therapeutic treatments of patients. This procedural skill requires practice and static phantom models are a commonly used education tool. Several commercial models that simulate blood vessels within tissue are available; however, they can be expensive. There are many examples of "Do-It-Yourself" models proposed; however, many of these require time to create the model. Mixing water and gelatin to make a gelatinous material, and the time necessary to set and store the phantom may deter people from pursuing these options. We propose Konnyaku jelly, or "yam cake," found in many Asian grocery stores, as the substrate to create a phantom model. When imaging with ultrasound, this model is similar to commercially available models, however the cost is less than $3.00 and preparation is about 5 min. We believe that Konnyaku jelly should be a more generally accepted homemade static model for phantom preparation.

Implementing a Statewide Prehospital Sepsis Protocol: Perspectives of Emergency Medical Services Medical Directors.

Background Sepsis is a medical emergency that requires prompt recognition and treatment. Multiple Emergency Medical Services (EMS) agencies across the United States have implemented sepsis protocols. In 2016, Maryland instituted its own state-wide EMS sepsis protocol which includes fluid resuscitation, vasopressor administration, and requires alerting the hospital of an incoming sepsis patient. Objective The purpose of this study was to quantify the perspectives of EMS medical directors in Maryland regarding prehospital sepsis care and to identify challenges encountered during the implementation of the statewide sepsis protocol. Methods A 17-question survey was sent to all 24 jurisdictional medical directors in the state of Maryland. Results A total of 14 (58%) medical directors responded, representing four of the five EMS regions in the state. More than half (57%) stated sepsis alerting was a priority in their jurisdiction; however, in a listing of eight initiatives, sepsis was the least prioritized. Most (64%) respondents believed their clinicians had adequate training on sepsis. A majority (79%) of medical directors surveyed felt that core measures of sepsis management would be beneficial. The potentially most helpful core measures were the volume of IV fluid administration (92%), true positive sepsis alerts (83%), and cases of failure to activate a sepsis alert (75%). Engagement of field personnel was rated as the biggest challenge for the implementation of a sepsis protocol in general, and lack of a thermometer on EMS units (50%) was the largest hurdle specifically in the 2016 statewide sepsis protocol. Surveyed medical directors (86%) believe the most difficult obstacle to overcome for EMS clinicians in the treatment of sepsis are nonspecific signs and symptoms. Conclusions Prehospital sepsis care was viewed to be important amongst the medical directors surveyed. However, significant challenges to implementation of a sepsis protocol and delivery of prehospital sepsis care are perceived by jurisdictional medical directors. Additional investment and dedication to sepsis care will advance prehospital sepsis treatment in Maryland.

Genetic model of MS severity predicts future accumulation of disability.

No genetic modifiers of multiple sclerosis (MS) severity have been independently validated, leading to a lack of insight into genetic determinants of the rate of disability progression. We investigated genetic modifiers of MS severity in prospectively acquired training (N = 205) and validation (N = 94) cohorts, using the following advances: (1) We focused on 113 genetic variants previously identified as related to MS severity; (2) We used a novel, sensitive outcome: MS Disease Severity Scale (MS-DSS); (3) Instead of validating individual alleles, we used a machine learning technique (random forest) that captures linear and complex nonlinear effects between alleles to derive a single Genetic Model of MS Severity (GeM-MSS). The GeM-MSS consists of 19 variants located in vicinity of 12 genes implicated in regulating cytotoxicity of immune cells, complement activation, neuronal functions, and fibrosis. GeM-MSS correlates with MS-DSS (r = 0.214; p = 0.043) in a validation cohort that was not used in the modeling steps. The recognized biology identifies novel therapeutic targets for inhibiting MS disability progression.

Intracellular production of hydrogels and synthetic RNA granules by multivalent molecular interactions.

Some protein components of intracellular non-membrane-bound entities, such as RNA granules, are known to form hydrogels in vitro. The physico-chemical properties and functional role of these intracellular hydrogels are difficult to study, primarily due to technical challenges in probing these materials in situ. Here, we present iPOLYMER, a strategy for a rapid induction of protein-based hydrogels inside living cells that explores the chemically inducible dimerization paradigm. Biochemical and biophysical characterizations aided by computational modelling show that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that acts as a size-dependent molecular sieve. We functionalize these polymers with RNA-binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. These results show that iPOLYMER can be used to synthetically reconstitute the nucleation of biologically functional entities, including RNA granules in intact cells.

Molecular-based diagnosis of multiple sclerosis and its progressive stage.

OBJECTIVE: Biomarkers aid diagnosis, allow inexpensive screening of therapies, and guide selection of patient-specific therapeutic regimens in most internal medicine disciplines. In contrast, neurology lacks validated measurements of the physiological status, or dysfunction(s) of cells of the central nervous system (CNS). Accordingly, patients with chronic neurological diseases are often treated with a single disease-modifying therapy without understanding patient-specific drivers of disability. Therefore, using multiple sclerosis (MS) as an example of a complex polygenic neurological disease, we sought to determine whether cerebrospinal fluid (CSF) biomarkers are intraindividually stable, cell type-, disease- and/or process-specific, and responsive to therapeutic intervention. METHODS: We used statistical learning in a modeling cohort (n = 225) to develop diagnostic classifiers from DNA-aptamer-based measurements of 1,128 CSF proteins. An independent validation cohort (n = 85) assessed the reliability of derived classifiers. The biological interpretation resulted from in vitro modeling of primary or stem cell-derived human CNS cells and cell lines. RESULTS: The classifier that differentiates MS from CNS diseases that mimic MS clinically, pathophysiologically, and on imaging achieved a validated area under the receiver operating characteristic curve (AUROC) of 0.98, whereas the classifier that differentiates relapsing-remitting from progressive MS achieved a validated AUROC of 0.91. No classifiers could differentiate primary progressive from secondary progressive MS better than random guessing. Treatment-induced changes in biomarkers greatly exceeded intraindividual and technical variabilities of the assay. INTERPRETATION: CNS biological processes reflected by CSF biomarkers are robust, stable, disease specific, or even disease stage specific. This opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders. Ann Neurol 2017;82:795-812.

Finger and foot tapping as alternative outcomes of upper and lower extremity function in multiple sclerosis.

BACKGROUND: While magnetic resonance imaging contrast-enhancing lesions represent an excellent screening tool for disease-modifying treatments in relapsing-remitting multiple sclerosis (RRMS), this biomarker is insensitive for testing therapies against compartmentalized inflammation in progressive multiple sclerosis (MS). Therefore, alternative sensitive outcomes are needed. Using machine learning, clinician-acquired disability scales can be combined with timed measures of neurological functions such as walking speed (e.g. 25-foot walk; 25FW) or fine finger movements (e.g. 9-hole peg test; 9HPT) into sensitive composite clinical scales, such as the recently developed combinatorial, weight-adjusted disability scale (CombiWISE). Ideally, these complementary simplified measurements of certain neurological functions could be performed regularly at patients' homes using smartphones. OBJECTIVES: We asked whether tests amenable to adaptation to smartphone technology, such as finger and foot tapping have comparable sensitivity and specificity to current non-clinician-acquired disability measures. RESULTS: We observed that finger and foot tapping can differentiate RRMS and progressive MS in a cross-sectional study and can also measure yearly and two-year disease progression in the latter, with better power (based on z-scores) in comparison to currently utilized 9HPT and 25FW. CONCLUSIONS: Replacing the 9HPT and 25FW with simplified tests broadly adaptable to smartphone technology may enhance the power of composite scales for progressive MS.

Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment.

Therapeutic advance in progressive multiple sclerosis (MS) has been very slow. Based on the transformative role magnetic resonance imaging (MRI) contrast-enhancing lesions had on drug development for relapsing-remitting MS, we consider the lack of sensitive outcomes to be the greatest barrier for developing new treatments for progressive MS. The purpose of this study was to compare 58 prospectively acquired candidate outcomes in the real-world situation of progressive MS trials to select and validate the best-performing outcome. The 1-year pre-treatment period of adaptively designed IPPoMS (ClinicalTrials.gov #NCT00950248) and RIVITaLISe (ClinicalTrials.gov #NCT01212094) Phase II trials served to determine the primary outcome for the subsequent blinded treatment phase by comparing 8 clinical, 1 electrophysiological, 1 optical coherence tomography, 7 MRI volumetric, 9 quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over 1 year (Δ) in the predetermined analysis and seven out of these were validated in two independent cohorts. Validated MRI outcomes had limited correlations with clinical scales, relatively poor signal-to-noise ratios (SNR) and recorded overlapping values between healthy subjects and MS patients with moderate-severe disability. Clinical measures correlated better, even though each reflects a somewhat different disability domain. Therefore, using machine-learning techniques, we developed a combinatorial weight-adjusted disability score (CombiWISE) that integrates four clinical scales: expanded disability status scale (EDSS), Scripps neurological rating scale, 25 foot walk and 9 hole peg test. CombiWISE outperformed all clinical scales (Δ = 9.10%; p = 0.0003) and all MRI outcomes. CombiWISE recorded no overlapping values between healthy subjects and disabled MS patients, had high SNR, and predicted changes in EDSS in a longitudinal assessment of 98 progressive MS patients and in a cross-sectional cohort of 303 untreated subjects. One point change in EDSS corresponds on average to 7.50 point change in CombiWISE with a standard error of 0.10. The novel validated clinical outcome, CombiWISE, outperforms the current broadly utilized MRI brain atrophy outcome and more than doubles sensitivity in detecting clinical deterioration in progressive MS in comparison to the scale traditionally used for regulatory approval, EDSS.