Molecular Profiling of Innate Immune Response Mechanisms in Ventilator-associated Pneumonia.

Ventilator-associated pneumonia (VAP) is a common hospital-acquired infection, leading to high morbidity and mortality. Currently, bronchoalveolar lavage (BAL) is used in hospitals for VAP diagnosis and guiding treatment options. Although BAL collection procedures are invasive, alternatives such as endotracheal aspirates (ETA) may be of diagnostic value, however, their use has not been thoroughly explored. Longitudinal ETA and BAL were collected from 16 intubated patients up to 15 days, of which 11 developed VAP. We conducted a comprehensive LC-MS/MS based proteome and metabolome characterization of longitudinal ETA and BAL to detect host and pathogen responses to VAP infection. We discovered a diverse ETA proteome of the upper airways reflective of a rich and dynamic host-microbe interface. Prior to VAP diagnosis by microbial cultures from BAL, patient ETA presented characteristic signatures of reactive oxygen species and neutrophil degranulation, indicative of neutrophil mediated pathogen processing as a key host response to the VAP infection. Along with an increase in amino acids, this is suggestive of extracellular membrane degradation resulting from proteolytic activity of neutrophil proteases. The metaproteome approach successfully allowed simultaneous detection of pathogen peptides in patients' ETA, which may have potential use in diagnosis. Our findings suggest that ETA may facilitate early mechanistic insights into host-pathogen interactions associated with VAP infection and therefore provide its diagnosis and treatment.

The Association Between Lateral Radiographs and Axial Computed Tomography of Posterior Malleolar Fractures as a Tool for Predicting Medial Malleolar Extension: A Multi-Center Retrospective Analysis.

Posterior malleolar fractures are often part of complex ankle fracture patterns. Radiographs and computed tomography are often obtained in the preoperative setting. In this study, we compared measurements from lateral ankle radiographs with measurements on axial computed tomography. We hypothesize that there is an association between measurements taken on lateral XR and certain fracture morphology such as medial extension and that measurements taken on lateral XR can be used to predict likelihood of medial extension type fractures. A multi-center retrospective analysis was performed involving patients with trimalleolar ankle fractures treated at two large urban healthcare systems ranging from January 1, 2010 to November 1, 2019. A total of 279 patients met criteria including 186 females and 93 males aged 18 to 90 with an average age 55. Four reviewers measured continuous variables on lateral radiograph and axial computed tomography: posterior malleolus fracture height, articular surface length, medial-lateral width, and anterior-posterior depth and then agreement was assessed via intraclass correlation coefficient. Pearson correlations were calculated for all pairwise combinations of measurements. Two fracture classification systems were then evaluated for association with the continuous variables. Lateral height was divided into quartiles and analyzed for the degree of association. Positive correlation was found between lateral height and axial depth/axial width. Taller lateral height values were statistically associated with medial extension type fractures. Lateral height 24.5mm-29.5mm is 3.1x higher, and lateral height >29.5mm is 8.6x more likely to have medial extension when compared to shorter lateral heights(<20.5mm). Based on these findings we suggest increased usage of pre-operative CT and evaluation for the use of posteromedial approaches in the setting of taller lateral height fracture patterns(>24.5mm) as seen on lateral XR.

Identification and quantitation of clinically relevant microbes in patient samples: Comparison of three k-mer based classifiers for speed, accuracy, and sensitivity.

Infections are a serious health concern worldwide, particularly in vulnerable populations such as the immunocompromised, elderly, and young. Advances in metagenomic sequencing availability, speed, and decreased cost offer the opportunity to supplement or even replace culture-based identification of pathogens with DNA sequence-based diagnostics. Adopting metagenomic analysis for clinical use requires that all aspects of the workflow are optimized and tested, including data analysis and computational time and resources. We tested the accuracy, sensitivity, and resource requirements of three top metagenomic taxonomic classifiers that use fast k-mer based algorithms: Centrifuge, CLARK, and KrakenUniq. Binary mixtures of bacteria showed all three reliably identified organisms down to 1% relative abundance, while only the relative abundance estimates of Centrifuge and CLARK were accurate. All three classifiers identified the organisms present in their default databases from a mock bacterial community of 20 organisms, but only Centrifuge had no false positives. In addition, Centrifuge required far less computational resources and time for analysis. Centrifuge analysis of metagenomes obtained from samples of VAP, infected DFUs, and FN showed Centrifuge identified pathogenic bacteria and one virus that were corroborated by culture or a clinical PCR assay. Importantly, in both diabetic foot ulcer patients, metagenomic sequencing identified pathogens 4-6 weeks before culture. Finally, we show that Centrifuge results were minimally affected by elimination of time-consuming read quality control and host screening steps.

Bariatric Arterial Embolization with Calibrated Radiopaque Microspheres and an Antireflux Catheter Suppresses Weight Gain and Appetite-Stimulating Hormones in Swine.

PURPOSE: To examine safety and efficacy of bariatric arterial embolization (BAE) with x-ray-visible embolic microspheres (XEMs) and an antireflux catheter in swine. MATERIAL AND METHODS: BAE with selective infusion of XEMs (n = 6) or saline (n = 4, control) into gastric fundal arteries was performed under x-ray guidance. Weight and plasma hormone levels were measured at baseline and weekly for 4 weeks after embolization. Cone-beam CT images were acquired immediately after embolization and weekly for 4 weeks. Hormone-expressing cells in the stomach were assessed by immunohistochemical staining. RESULTS: BAE pigs lost weight 1 week after embolization followed by significantly impaired weight gain relative to control animals (14.3% vs 20.9% at 4 weeks, P = .03). Plasma ghrelin levels were significantly lower in BAE pigs than in control animals (1,221.6 pg/mL vs 1,706.2 pg/mL at 4 weeks, P < .01). XEMs were visible on x-ray and cone-beam CT during embolization, and radiopacity persisted over 4 weeks (165.5 HU at week 1 vs 158.5 HU at week 4, P = .9). Superficial mucosal ulcerations were noted in 1 of 6 BAE animals. Ghrelin-expressing cell counts were significantly lower in the gastric fundus (17.7 vs 36.8, P < .00001) and antrum (24.2 vs 46.3, P < .0001) of BAE pigs compared with control animals. Gastrin-expressing cell counts were markedly reduced in BAE pigs relative to control animals (98.5 vs 127.0, P < .02). Trichrome staining demonstrated significantly more fibrosis in BAE animals compared with control animals (13.8% vs 8.7%, P < .0001). CONCLUSIONS: XEMs enabled direct visualization of embolic material during and after embolization. BAE with XEMs and antireflux microcatheters was safe and effective.

Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands.

BACKGROUND: Between 1992 and 2011, 373 Canadian individuals with adverse anesthetic reaction were referred to the Malignant Hyperthermia Unit in Toronto, Ontario, Canada for malignant hyperthermia (MH) diagnostic testing. We analyzed the epidemiologic characteristics of the index adverse anesthetics for those probands who were confirmed to be MH susceptible. METHODS: One hundred twenty-nine proband survivors of adverse anesthetic reactions, whose MH susceptible status was confirmed by caffeine-halothane contracture testing were selected. Individuals were excluded if the index anesthetic record was not available for review. Data regarding demographics, clinical signs, laboratory findings, treatment, and complications were retrospectively compiled and analyzed. A Fisher exact test and χ test were applied to compare categorical variables. The Wilcoxon rank-sum test was applied with continuous variables. RESULTS: Young males (61.2%) dominated among selected patients. Seventeen of 129 (13.2%) patients had prior unremarkable anesthesia. Anesthetic triggers were volatile-only (n = 58), succinylcholine-only (n = 20), or both volatile and succinylcholine (n = 51). Eight (6.2%) cases occurred in the postanesthetic care unit. There were no reactions after discharge from the postanesthetic care unit. The most frequent clinical signs were hyperthermia (66.7%), sinus tachycardia (62.0%), and hypercarbia (51.9%). Complications occurred in 20.1% of patients, the most common complication being renal dysfunction. When 20 or more minutes between the first adverse sign and dantrolene treatment elapsed, complication rates increased to ≥30%. CONCLUSIONS: This is the first Canadian study in 3 decades to report nationwide data on MH epidemiology. Features that differ from earlier reports include a 15.5% incidence of reactions triggered by succinylcholine alone and lower complication rates. In agreement with previously published studies, we confirmed in this independent dataset that increased complication rates were associated with an increased time interval between the first adverse clinical sign and dantrolene treatment. This underscores the need for early diagnosis and rapid dantrolene access and administration in anesthetizing locations using either succinylcholine or volatile anesthetic drugs.

Pars plana Ahmed valve and vitrectomy in patients with glaucoma associated with posterior segment disease.

PURPOSE: To assess the safety and efficacy of a modified technique for pars plana placement of the Ahmed valve in combination with pars plana vitrectomy in the treatment of glaucoma associated with posterior segment disease. METHODS: Thirty-nine eyes with glaucoma associated with posterior segment disease underwent pars plana vitrectomy combined with Ahmed valve placement. All valves were placed in the pars plana using a modified technique, without the pars plana clip, and using a scleral patch graft. RESULTS: The 24 eyes diagnosed with neovascular glaucoma had an improvement in intraocular pressure from 37.6 mmHg to 13.8 mmHg and best-corrected visual acuity from 2.13 logarithm of minimum angle of resolution to 1.40 logarithm of minimum angle of resolution. Fifteen eyes diagnosed with steroid-induced glaucoma had an improvement in intraocular pressure from 27.9 mmHg to 14.1 mmHg and best-corrected visual acuity from 1.38 logarithm of minimum angle of resolution to 1.13 logarithm of minimum angle of resolution. Complications included four cases of cystic bleb formation and one case of choroidal detachment and explantation for hypotony. CONCLUSION: Ahmed valve placement through the pars plana during vitrectomy is an effective option for managing complex cases of glaucoma without the use of the pars plana clip.

Virtual reality consumer product injuries: An analysis of national emergency department data.

INTRODUCTION: The growing popularity of virtual reality devices and increasingly widespread distribution of VR products into the home exposes users to risk of bodily harm. Safety features are integrated into the devices themselves, but the burden of cautious use rests upon the end user. The purpose of this study is to quantify and describe the array of injuries and demographics effected by the burgeoning VR industry to inform and encourage mitigation strategies. MATERIALS AND METHODS: The National Electronic Injury Surveillance System (NEISS) data was used to examine a nationwide sample of emergency department records from 2013 - 2021. Inverse probability sample weights for cases were applied to arrive at national estimates. NEISS data included consumer product injuries, patient age, sex, race and ethnicity, drug and alcohol involvement, diagnoses, injury descriptions, and emergency department disposition. RESULTS: The first VR-related injury was reported in the NEISS data in 2017, and injuries were estimated to number 125. Incidents of VR-related injuries amplified as increased VR units sold, and by 2021, there was a 352% increase in VR injuries totaling a weighted estimate of 1,336 ED visits. The most common VR-related injury diagnosis is fracture (30.3%), followed by laceration (18.6%), contusion (13.9%), other (11.8%), and strain / sprain (10.0%). VR-related injuries involve the hand (12.1%), face (11.5%), finger (10.6%), and knee (9.0%), head (7.0%) and upper trunk (7.0%). Patients age 0-5 most commonly experienced injuries to the face (62.3%). Injuries in patients 6-18 were mostly to the hand (22.3%) and face (12.8%). Patients 19-54 experienced primarily injuries to the knee (15.3%), finger (13.5%), and wrist (13.3%). Patients aged 55 and older disproportionately experienced injuries in the upper trunk (49.1%) and upper arm (25.2%). CONCLUSIONS: This is the first study to describe the incidence, demographics and characteristics of injuries from VR device use. Sales of home VR units continue to increase annually and the rapid increase in VR consumer injuries is being managed by emergency departments across the country. An understanding of these injuries will inform VR manufacturers, application developers, and users to promote safe product development and operation.

Potential long-term benefits of acute hypothermia after spinal cord injury: assessments with somatosensory-evoked potentials.

OBJECTIVE: Neuroprotection by hypothermia has been an important research topic over last two decades. In animal models of spinal cord injury, the primary focus has been assessing the effects of hypothermia on behavioral and histologic outcomes. Although a few studies have investigated electrophysiological changes in descending motor pathways with motor-evoked potentials recorded during cooling, we report here hypothermia induced increased electrical conduction in the ascending spinal cord pathways with somatosensory-evoked potentials in injured rats. In our experiments, these effects lasted long after the acute hypothermia and were accompanied by potential long-term improvements in motor movement. DESIGN: Laboratory investigation. SETTING: University medical school. SUBJECTS: Twenty-one female Lewis rats. INTERVENTIONS: Hypothermia. MEASUREMENTS AND MAIN RESULTS: All animals underwent spinal cord contusion with the NYU-Impactor by a 12.5-mm weight drop at thoracic vertebra T8. A group (n = 10) was randomly assigned for a systemic 2-hr hypothermia episode (32 ± 0.5°C) initiated approximately 2.0 hrs postinjury. Eleven rats were controls with postinjury temperature maintained at 37 ± 0.5°C for 2 hrs. The two groups underwent preinjury, weekly postinjury (up to 4 wks) somatosensory-evoked potential recordings and standard motor behavioral tests (BBB). Three randomly selected rats from each group were euthanized for histologic analysis at postinjury day 3 and day 28. Compared with controls, the hypothermia group showed significantly higher postinjury somatosensory-evoked potential amplitudes with longer latencies. The BBB scores were also higher immediately after injury and 4 wks later in the hypothermia group. Importantly, specific changes in the Basso, Beattie, Bresnahan scores in the hypothermia group (not seen in controls) indicated regained functions critical for motor control. Histologic evaluations showed more tissue preservation in the hypothermia group. CONCLUSIONS: After spinal cord injury, early systemic hypothermia provided significant neuroprotection weeks after injury through improved sensory electrophysiological signals in rats. This was accompanied by higher motor behavioral scores and more spared tissue in acute and postacute periods after injury.

Liquid biopsy, using a novel DNA methylation signature, distinguishes pancreatic adenocarcinoma from benign pancreatic disease.

We tested the ability of a novel DNA methylation biomarker set to distinguish metastatic pancreatic cancer cases from benign pancreatic cyst patients and to monitor tumor dynamics using quantitative DNA methylation analysis of cell-free DNA (cfDNA) from blood samples. The biomarkers were able to distinguish malignant cases from benign disease with high sensitivity and specificity (AUC = 0.999). Furthermore, the biomarkers detected a consistent decline in tumor-derived cfDNA in samples from patients undergoing chemotherapy. The study indicates that our liquid biopsy assay could be useful for management of pancreatic cancer patients.

Blunt traumatic occult pneumothorax: is observation safe?--results of a prospective, AAST multicenter study.

BACKGROUND: An occult pneumothorax (OPTX) is found incidentally in 2% to 10% of all blunt trauma patients. Indications for intervention remain controversial. We sought to determine which factors predicted failed observation in blunt trauma patients. METHODS: A prospective, observational, multicenter study was undertaken to identify patients with OPTX. Successfully observed patients and patients who failed observation were compared. Multivariate logistic regression was used to identify predictors of failure of observation. OPTX size was calculated by measuring the largest air collection along a line perpendicular from the chest wall to the lung or mediastinum. RESULTS: Sixteen trauma centers identified 588 OPTXs in 569 blunt trauma patients. One hundred twenty-one patients (21%) underwent immediate tube thoracostomy and 448 (79%) were observed. Twenty-seven patients (6%) failed observation and required tube thoracostomy for OPTX progression, respiratory distress, or subsequent hemothorax. Fourteen percent (10 of 73) failed observation during positive pressure ventilation. Hospital and intensive care unit lengths of stay, and ventilator days were longer in the failed observation group. OPTX progression and respiratory distress were significant predictors of failed observation. Most patient deaths were from traumatic brain injury. Fifteen percentage of patients in the failed observation group developed complications. No patient who failed observation developed a tension PTX, or experienced adverse events by delaying tube thoracostomy. CONCLUSION: Most blunt trauma patients with OPTX can be carefully monitored without tube thoracostomy; however, OPTX progression and respiratory distress are independently associated with observation failure.

Critical traumatic brain injury is associated with worse coagulopathy.

OBJECTIVES: As thromboelastography (TEG) becomes the standard of care in patients with hemorrhagic shock (HS), an association between concomitant traumatic brain injury (TBI) and coagulopathy by TEG parameters is not well understood and is thus investigated. METHODS: Retrospective analysis of trauma registry data at a single level 1 trauma center of 772 patients admitted with head Abbreviated Injury Scale (AIS) score of 3 and TEG studies between 2014 and 2017. Patients were stratified to moderate-severe TBI by head AIS scores of 3 and 4 (435 patients) and critical TBI by head AIS score of 5 (328 patients). Hemorrhagic shock was defined by base deficit of 4 or shock index of 0.9. Statistical analysis with unpaired t tests compared patients with critical TBI with patients with moderate-severe TBI, and patients were grouped by presence or absence of HS. A comparison of TBI data with conventional coagulation studies was also evaluated. RESULTS: In the setting of HS, critical TBI versus moderate-severe TBI was associated with longer R time (p = 0.004), longer K time (p < 0.05), less acute angle (p = 0.001), and lower clot strength and stability (maximum amplitude [MA]) (p = 0.01). Worse TBI did not correlate with increased fibrinolysis by clot lysis measured by the percentage decrease in amplitude at 30 minutes after MA (p = 0.3). Prothrombin time and international normalized ratio failed to demonstrate more severe coagulopathy, while partial thromboplastin time was found to correlate with severity of TBI (p = 0.01). In patients with critical TBI, the presence of HS correlated with a statistically significant worsening of all parameters (p < 0.05) except for clot lysis measured by the percentage decrease in amplitude at 30 minutes after MA (LY-30). CONCLUSION: Thromboelastography demonstrates that, with and without hemorrhagic shock, critical TBI correlates with a significant worsening of traumatic coagulopathy in comparison with moderate/severe TBI. In HS, critical TBI correlates with impaired clot initiation, impaired clot kinetics, and impaired platelet-associated clot strength and stability versus parameters found in moderate-severe TBI. Hemorrhagic shock correlates with worse traumatic coagulopathy in all evaluated patient groups with TBI. Conventional coagulation studies underestimate TBI-associated coagulopathy. Traumatic brain injury-associated coagulopathy is not associated with fibrinolysis. LEVEL OF EVIDENCE: Prognostic/epidemiological, level IV; prognostic/epidemiological, level III.

Microfluidic-prepared, monodisperse, X-ray-visible, embolic microspheres for non-oncological embolization applications.

Embolotherapy using particle embolics is normally performed with exogenous contrast to assist in visualization. However, the exact location of the embolics cannot be identified after contrast washout. We developed a novel, pseudo-check valve-integrated microfluidic device, that partitions barium- impregnated alginate from crosslinking solution, thereby preventing nozzle failure. This enables rapid and continuous generation of inherently X-ray-visible embolic microspheres (XEMs) with uniform size. The XEMs are visible under clinical X-ray and cone beam CT both in vitro and in vivo. In particular, we demonstrated the embolization properties of these XEMs in large animals, performing direct intra- and post-procedural assessment of embolic delivery. The persistent radiopacity of these XEMs enables real-time evaluation of embolization precision and offers great promise for non-invasive follow-up examination without exogenous contrast. We also demonstrated that bariatric arterial embolization with XEMs significantly suppresses weight gain in swine, as an example of a non-oncological application of embolotherapy.

Thromboembolic prophylaxis in blunt traumatic intracranial hemorrhage: a retrospective review.

There are few data in the literature on venous thromboembolic (VTE) prophylaxis for the traumatic population with intracranial hemorrhage (ICH). We reviewed our institutional experience and compared the incidence of deep vein thrombosis and pulmonary embolism in patients with ICH receiving either early prophylaxis (< 72 hours from admission) or late prophylaxis (> 72 hours from admission), and the respective incidences in progression of intracranial hemorrhage. We identified 124 patients for this study. There were 29 patients (23%) who received early (< 72 hours) pharmacological VTE prophylaxis and 53 patients (43%) received late (> 72 hours) prophylaxis. In the study, 42 patients had intermittent pneumatic compression devices and received no pharmacological VTE prophylaxis. Among those with pharmacological VTE prophylaxis, 10 patients (8%) developed VTE (9 deep vein thrombosis and 1 pulmonary embolism). Three patients with pharmacological VTE prophylaxis developed ICH progression, with one being clinically significant. Our institutional review demonstrated that it seems safe to initiate early pharmacological VTE prophylaxis in blunt head trauma with stable ICH. Nevertheless, further prospective randomized studies are needed to fully elucidate the safety and efficacy in the timing of prophylaxis for blunt head trauma with ICH.

Hypericum perforatum extract modulates cortical plasticity in humans.

BACKGROUND: Hypericum perforatum (HYP) extract is one of the most commonly used complementary alternative medicines (CAMs) for the treatment of mild-to-moderate depression. Non-invasive brain stimulation protocols can be used to investigate the effect of psychoactive substances on the human brain. In this study, we explored the effect of a single dose of HYP extract (WS 5570) intake on corticospinal excitability and plasticity in humans. METHODS: Twenty-eight healthy subjects were required to intake 900 mg of either HYP extract or placebo. Cortical excitability was assessed using single and paired transcranial magnetic stimulation (TMS). The electrophysiological parameters of motor threshold, recruitment of motor-evoked potentials (MEPs), cortical silent period (CSP), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were tested before and 2 and 5 h after the oral intake. Spinal and neuromuscular excitability and peripheral nerve excitability were measured by F response and M-wave. Cortical plasticity was induced using transcranial direct current stimulation (tDCS). Subjects received either HYP extract or placebo before anodal and cathodal tDCS of the primary motor cortex. Plasticity was assessed by MEP amplitudes. RESULTS: HYP extract reversed cathodal tDCS-induced long-term depression (LTD)-like plasticity into facilitation, as compared to placebo. HYP extract did not have a significant effect on anodal tDCS-induced plasticity and TMS measures of motor cortex and spinal/neuromuscular excitability. CONCLUSIONS: Our findings suggest that a single oral dose of HYP extract modulates cortical plasticity in healthy subjects and provide new insight into its possible mechanism of action in humans.

Active immunity induced by passive IgG post-exposure protection against ricin.

Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab')2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were observed between IgG and F(ab')2 when compared at the same molar concentration. In a murine ricin intoxication model, both IgG and F(ab')2 could rescue 100% of the mice by one dose (3 nmol) administration of antibodies 1 hour after 5 × LD50 ricin challenge. Nine days later, when the rescued mice received a second ricin challenge (5 × LD50), only the IgG-treated mice survived; the F(ab')2-treated mice did not. The experimental design excluded the possibility of residual goat IgG responsible for the protection against the second ricin challenge. Results confirmed that the active immunity against ricin in mice was induced quickly following the passive delivery of a single dose of goat IgG post-exposure. Furthermore, it was demonstrated that the induced active immunity against ricin in mice lasted at least 5 months. Therefore, passive IgG therapy not only provides immediate protection to the victim after ricin exposure, but also elicits an active immunity against ricin that subsequently results in long term protection.

New and emerging drugs and targets for type 2 diabetes: reviewing the evidence.

BACKGROUND: Diabetes is a deadly and costly disease. The number of adults in the United States with newly diagnosed diabetes has nearly tripled from 1980 to 2011. At the current pace, 1 in 3 US adults will have diabetes in their lifetime. Currently, 14 classes of drugs are available to treat type 2 diabetes mellitus, but only 36% of patients with type 2 diabetes achieve glycemic control with the currently available therapies. Therefore, new treatment options are desperately needed. DISCUSSION: Despite the availability of many pharmacotherapies, in 2011 an estimated 3.1 million (14.9%) patients with type 2 diabetes still reported not taking medications to treat their diabetes. Patient compliance is a major obstacle facing practicing clinicians on a daily basis. New treatment options are desperately needed, but efficacy and tolerability are no longer the only criteria contributing to the success of a drug. Ease of administration, convenient dosing frequency, being weight control friendly, and having a low risk for hypoglycemia are important factors for the survival of a new drug in the US healthcare system. The present review is focused on important new drugs and drug classes in the pipeline, as well as on recently approved drugs, including sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 agents, and new insulin therapies, as well as on the technologic improvements in the delivery and dosing frequency of some of the currently available drugs. CONCLUSIONS: In the United States, diabetes can be expected to continue to wreak significant human and financial tolls. The associated complications will continue to climb if they are not controlled and stopped. New therapies for diabetes are clearly needed that will better address these unmet needs. The common threads among the emerging therapies are their convenience of administration and dosing frequency, which are important to the improvement of patient adherence.

Conformation-dependent high-affinity potent ricin-neutralizing monoclonal antibodies.

Ricin is a potential biothreat agent with no approved antidote available for ricin poisoning. The aim of this study was to develop potent antibody-based antiricin antidotes. Four strong ricin resistant hybridoma clones secreting antiricin monoclonal antibodies (mAbs) were developed. All four mAbs are bound to conformational epitopes of ricin toxin B (RTB) with high affinity (KD values from 2.55 to 36.27 nM). RTB not only triggers cellular uptake of ricin, but also facilitates transport of the ricin toxin A (RTA) from the endoplasmic reticulum to the cytosol, where RTA exerts its toxic activity. The four mAbs were found to have potent ricin-neutralizing capacities and synergistic effects among them as determined by an in vitro neutralization assay. In vivo protection assay demonstrated that all four mAbs had strong efficacy against ricin challenges. D9 was found to be exceptionally effective. Intraperitoneal (i.p.) administration of D9, at a dose of 5 µ g, 6 weeks before or 6 hours after an i.p. challenge with 5 × LD50 of ricin was able to protect or rescue 100% of the mice, indicating that mAb D9 is an excellent candidate to be developed as a potent antidote against ricin poisoning for both prophylactic and therapeutic purposes.

Mechanical ventilation weaning and extubation after spinal cord injury: a Western Trauma Association multicenter study.

BACKGROUND: Respiratory failure after acute spinal cord injury (SCI) is well recognized, but data defining which patients need long-term ventilator support and criteria for weaning and extubation are lacking. We hypothesized that many patients with SCI, even those with cervical SCI, can be successfully managed without long-term mechanical ventilation and its associated morbidity. METHODS: Under the auspices of the Western Trauma Association Multi-Center Trials Group, a retrospective study of patients with SCI at 14 major trauma centers was conducted. Comprehensive injury, demographic, and outcome data on patients with acute SCI were compiled. The primary outcome variable was the need for mechanical ventilation at discharge. Secondary outcomes included the use of tracheostomy and development of acute lung injury and ventilator-associated pneumonia. RESULTS: A total of 360 patients had SCI requiring mechanical ventilation. Sixteen patients were excluded for death within the first 2 days of hospitalization. Of the 344 patients included, 222 (64.5%) had cervical SCI. Notably, 62.6% of the patients with cervical SCI were ventilator free by discharge. One hundred forty-nine patients (43.3%) underwent tracheostomy, and 53.7% of them were successfully weaned from the ventilator, compared with an 85.6% success rate among those with no tracheostomy (p < 0.05). Patients who underwent tracheostomy had significantly higher rates of ventilator-associated pneumonia (61.1% vs. 20.5%, p < 0.05) and acute lung injury (12.8% vs. 3.6%, p < 0.05) and fewer ventilator-free days (1 vs. 24 p < 0.05). When controlled for injury severity, thoracic injury, and respiratory comorbidities, tracheostomy after cervical SCI was an independent predictor of ventilator dependence with an associated 14-fold higher likelihood of prolonged mechanical ventilation (odds ratio, 14.1; 95% confidence interval, 2.78-71.67; p < 0.05). CONCLUSION: While many patients with SCI require short-term mechanical ventilation, the majority can be successfully weaned before discharge. In patients with SCI, tracheostomy is associated with major morbidity, and its use, especially among patients with cervical SCI, deserves further study. LEVEL OF EVIDENCE: Prognostic study, level III.

Association of changes in the use of board-certified critical care intensivists with mortality outcomes for trauma patients at a well-established level I urban trauma center.

BACKGROUND: An intensivist-directed Intensive Care Unit is a closed-model unit in which a physician formally trained in critical care plays a leadership role in patient management. In the last decade, there has been a move toward closed Intensive Care Units. The purpose of this evaluation was to assess the association of changes in the use of intensivists to a closed-model with mortality outcomes in injured patients seen in a long-established urban Level I Trauma Center. METHODS: This analysis used data from the Scottsdale Healthcare Osborn Medical Center trauma registry from January 1, 2002-December 31, 2008. Mortality prior to hospital discharge was compared in the pre-intensivist (intensivists were not employed and did not provide care), partial intensivist (intensivists were employed and provided care during some Intensive Care Unit shifts) and full-time intensivist (intensivists were employed and provided care in the Intensive Care Unit full time) periods. Multiple logistic regression analysis was used to estimate odds ratios for mortality adjusting for patient characteristics and injury severity for the partial intensivist and full-time intensivist periods compared with the pre-intensivist period. RESULTS: Of 18,918 patients, 365 (1.9%) died before hospital discharge. After adjustment for demographic factors and injury severity score, for all patients, odds ratios comparing the partial intensivist and full-intensivist periods with the pre-intensivist period were 0.84 (95% confidence interval 0.64-1.11) and 0.99 (95% confidence interval 0.69-1.41). In patients with an injury severity score 16-24, the adjusted OR for death was 0.20 (95% CI 0.07-0.58) comparing the partial-intensivist with the pre-intensivist period and 0.30 (95% CI 0.11-0.88) comparing the full-time intensivist period with the pre-intensivist period. For patients age 65 + years, compared with the pre-intensivist period, odds ratio were 0.51 (95% confidence interval 0.31-0.84) and 0.61 (95% confidence interval 0.32-1.16) for the partial and full-time intensivist periods respectively. CONCLUSIONS: In our setting, a change to a closed Intensive Care Unit model was associated with improved mortality outcomes in patients with less severe injuries and patients age 65+ years.

Human embryonic stem cell-derived oligodendrocyte progenitors aid in functional recovery of sensory pathways following contusive spinal cord injury.

BACKGROUND: Transplantations of human stem cell derivatives have been widely investigated in rodent models for the potential restoration of function of neural pathways after spinal cord injury (SCI). Studies have already demonstrated cells survival following transplantation in SCI. We sought to evaluate survival and potential therapeutic effects of transplanted human embryonic stem (hES) cell-derived oligodendrocyte progenitor cells (OPCs) in a contusive injury in rats. Bioluminescence imaging was utilized to verify survivability of cells up to 4 weeks, and somatosensory evoked potential (SSEPs) were recorded at the cortex to monitor function of sensory pathways throughout the 6-week recovery period. PRINCIPAL FINDINGS: hES cells were transduced with the firefly luciferase gene and differentiated into OPCs. OPCs were transplanted into the lesion epicenter of rat spinal cords 2 hours after inducing a moderate contusive SCI. The hES-treatment group showed improved SSEPs, including increased amplitude and decreased latencies, compared to the control group. The bioluminescence of transplanted OPCs decreased by 97% in the injured spinal cord compared to only 80% when injected into an uninjured spinal cord. Bioluminescence increased in both experimental groups such that by week 3, no statistical difference was detected, signifying that the cells survived and proliferated independent of injury. Post-mortem histology of the spinal cords showed integration of human cells expressing mature oligodendrocyte markers and myelin basic protein without the expression of markers for astrocytes (GFAP) or pluripotent cells (OCT4). CONCLUSIONS: hES-derived OPCs transplanted 2 hours after contusive SCI survive and differentiate into OLs that produce MBP. Treated rats demonstrated functional improvements in SSEP amplitudes and latencies compared to controls as early as 1 week post-injury. Finally, the hostile injury microenvironment at 2 hours post-injury initially caused increased cell death but did not affect the long-term cell proliferation or survival, indicating that cells can be transplanted sooner than conventionally accepted.