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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.

Non-membrane bound, hydrogel-like entities, such as RNA granules, nucleate essential cellular functions through their unique physico-chemical properties. However, these intracellular hydrogels have not been as extensively studied as their extracellular counterparts, primarily due to technical challenges in probing these materials in situ. Here, by taking advantage of a chemically inducible dimerization paradigm, we developed iPOLYMER, a strategy for rapid induction of protein-based hydrogels inside living cells. A series of biochemical and biophysical characterizations, in conjunction with computational modeling, revealed that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that behaves as a size-dependent molecular sieve. We studied several properties of the gel and functionalized it with RNA binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. Therefore, we here demonstrate that iPOLYMER presents a unique and powerful approach to synthetically reconstitute hydrogel-like structures including RNA granules in intact cells.

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 if cerebrospinal fluid (CSF) biomarkers are intra-individually 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 1128 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 receiver-operator characteristic curve (AUROC) of 0.98, while the classifier that differentiates relapsing-remitting from progressive MS achieved a validated AUROC of 0.91. No classifiers could differentiate primary- from secondary-progressive MS better than random guessing. Treatment-induced changes in biomarkers greatly exceeded intra-individual- and technical variabilities of the assay. Interpretation: CNS biological processes reflected by CSF biomarkers are robust, stable, and disease- or even disease-stage specific. This opens opportunities for broad utilization of CSF biomarkers in drug development and precision medicine for CNS disorders. This article is protected by copyright. All rights reserved.

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.

Non-membrane bound, hydrogel-like entities, such as RNA granules, nucleate essential cellular functions through their unique physico-chemical properties. However, these intracellular hydrogels have not been as extensively studied as their extracellular counterparts, primarily due to technical challenges in probing these materialsin situ.Here, by taking advantage of a chemically inducible dimerization paradigm, we developed iPOLYMER, a strategy for rapid induction of protein-based hydrogels inside living cells. A series of biochemical and biophysical characterizations, in conjunction with computational modeling, revealed that the polymer network formed in the cytosol resembles a physiological hydrogel-like entity that behaves as a size-dependent molecular sieve. We studied several properties of the gel and functionalized it with RNA binding motifs that sequester polyadenine-containing nucleotides to synthetically mimic RNA granules. Therefore, we here demonstrate that iPOLYMER presents a unique and powerful approach to synthetically reconstitute hydrogel-like structures including RNA granules in intact cells.

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.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.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.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.

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 one 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 eight clinical, one electrophysiological, one optical coherence tomography, seven MRI volumetric, nine quantitative T1 MRI, and 32 diffusion tensor imaging MRI outcomes. Fifteen outcomes demonstrated significant progression over one 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 optimization, 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 nine 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 standard error of 0.10. A 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.

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.

M. Tanigawa , M. Maruyama , M. Sugiki , K. Shimaya , K. Anai and H. Mihara . Clearance and distribution of a haemorrhagic factor purified from Bothrops jararaca venom in mice. Toxicon 32, 583–593, 1994.—We previously purified two fibrinolytic/haemorrhagic enzymes (jararafibrase-I and II) from Bothrops jararaca venom. In the present study, the clearance, organ distribution and local absorption rate were examined in mice using 125 I-labelled jararafibrase-I. Following intravenous injection of 125 I-labelled jararafibrase-I, a complex was rapidly formed with the plasma protein and the radioactivity quickly disappeared from the circulation with a half-life of about 3 min for the initial part of the curve. The highest level of the radioactivity (59.5%) was seen in the liver at 5 min after dosing, and the next highest level of radioactivity (14.4%) was seen in the kidney at 60 min after dosing. At 60 min after dosing, 36.8% of the total injected radioactivity was seen in the contents of the small intestine, and 11.4% of the total injected radioactivity was seen in the contents of the large intestine at 120 min after dosing. It is assumed that the jararafibrase-I was metabolized mainly in the liver, to small mol. wt products, and excreted in the intestine via the bile duct. Also, a small amount of jararafibrase-I appeared to be metabolized in the kidney. Following subcutaneous injection, a high-dose group revealed a low local absorption rate. The low local absorption rate was apparently due to a diminished blood flow caused by subcutaneous haemorrhage.

We previously reported (Shimaya et al. (1992) Enzyme, 46, 204) that a rapid and strong increase of plasminogen activator (PA) was induced during anaphylaxis, and that the main plasma fibrinolytic enzyme which increased in the anaphylaxis group was shown to be tissue-type plasminogen activator (t-PA). Anaphylaxis was induced in rabbits by giving BSA after t-AMCHA injection. 44% of those rabbits died within 3 h after BSA injection. In the dead group, the euglobulin fibrinolytic activity (EFA) could not be detected by the plasminogen-rich fibrin plate method and the t-PA activity, using the natural substrate plasminogen, did not rise significantly reaching a peak at 10–15 min. However, the EFA and t-PA activity increased significantly in the surviving group. A significant prolongation of the activated partial thromboplastin time (AFTT) and the prothrombin time (PT) was observed during anaphylaxis in both groups. These findings suggest that increased PA activity during anaphylaxis is an important defe...

This paper describes a novel i-line lithography by phase-shifting on the substrate (POST). With POST, 0.2?m resist patterns have been achieved by using an i-line stepper and conventional masks without phase shifters. It was confirmed that fine patterns were formed by the phase-shifting effect in the resist on the substrate. Simulation suggests that POST has a better resolution than a phase-shifting mask. This method consists of simple processes and is expected to be useful in the fabrication of deep-submicron patterns for ULSI.

症例は61歳,男性.慢性膵炎,膵仮性嚢胞,糖尿病の診断にて入院.入院中突然の腹痛と腹部腫瘤が出現,内視鏡, US, CTから膵仮性嚢胞からの出血により胃粘膜下に巨大な血腫を形成したものと診断.保存的に経過をみていたところ,胃壁に痩孔ができ,血腫は,徐々に消退していった.膵仮性嚢胞からの出血と,血腫の消退までの自然経過を各種画像検査で追えた症例はまれであり報告した.

The solvent extraction of alkali metal ions by crown ethers was studied in a cell of constant interfacial area. The influence on the extraction rates o