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Patient-focused drug development (PFDD) represents a transformative approach that is reshaping the pharmaceutical landscape by centering on patients throughout the drug development process. Recent advancements in Artificial Intelligence (AI), especially in Natural Language Processing (NLP), have enabled the analysis of vast social media datasets, also called Social Media Listening (SML), providing insights not only into patient perspectives but also into those of other interest groups such as caregivers. In this method study, we propose an NLP framework that-given a particular disease-is designed to extract pertinent information related to three primary research topics: identification of interest groups, understanding of challenges, and assessing treatments and support systems. Leveraging external resources like ontologies and employing various NLP techniques, particularly zero-shot text classification, the presented framework yields initial meaningful insights into these research topics with minimal annotation effort., Competing Interests: VM was an Independent Researcher. MK, MJ, MR, VS, and ES were employed by the Know Center Research GmbH. MV, GM, SN, RG, and RM were employed by the Chiesi Farmaceutici SpA., (Copyright © 2025 Matoshi, De Vuono, Gaspari, Kröll, Jantscher, Nicolardi, Mazzola, Rauch, Sabol, Salhofer and Mariani.)

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Objectives: Cardiac arrest patients with a shockable rhythm are more likely to survive an out-of-hospital cardiac arrest (OHCA) compared with a nonshockable rhythm. An electrocardiogram (ECG) is the most common way to identify a shockable rhythm, but it can miss patients with clinically significant ventricular fibrillation (vfib). We sought to determine the percentage of nonshockable OHCA patients that demonstrated vfib on echo., Methods: Secondary analysis of echo images recorded from a prior study from our group, Real-Time Evaluation and Assessment for Sonography-Outcomes Network (REASON), a multicenter, observational study of OHCA patients presenting to the emergency department with nonshockable rhythms. Using ECG and echocardiogram images recorded during the initial cardiopulmonary resuscitation (CPR) pause, 2 independent emergency physicians determined the presence of vfib. Two experienced emergency physicians (R.G. and T.G.) reviewed echo images with adjudication by a third if necessary. ECG interpretation was unblinded to patient information. The primary outcome was the proportion of patients in occult vfib., Results: During the first CPR pause, reviewers noted occult vfib in 22/685 (3.2%; 95% CI, 2.1%-4.8%) subjects. Patients with ECG vfib (n = 55) were defibrillated immediately during the first pause in CPR, but no patients with occult vfib during the first pause in CPR were defibrillated. Subsequently, 50% (11 of 22) of occult vfib patients were defibrillated when ECG vfib was recognized during an ensuing pause in CPR., Conclusion: One in 33 OHCAs with a nonshockable ECG rhythm exhibits VF on echocardiogram. Patients presenting to the emergency department in a presumed nonshockable rhythm following OHCA may benefit from prompt defibrillation if personnel recognize occult vfib on echo., Competing Interests: S.A. has book royalties from Springer and is a paid consultant for General Electric and EXO ultrasound. R.G. was a paid consultant to Butterfly Ultrasound Inc. The other authors have affirmed they have no conflicts of interest to declare., (© 2024 The Authors.)

Background : Hepatic dysfunction (HD) after liver transplantation (LT) or extended hepatic resection (EHR) is associated with graft failure and high short-term mortality. We evaluated the safety and depurative efficacy of CytoSorb® in these settings. The primary endpoint was the change in serum total bilirubin at the end of the treatment compared to the baseline value. The secondary endpoint was to evaluate the trend of serum total bilirubin and coagulation parameters up to 72 h after discontinuation of CytoSorb®. The effects of CytoSorb® therapy on the degree of hepatic encephalopathy (HE), Sequential Organ Failure Assessment (SOFA), and Model for End-Stage Liver Disease (MELD) scores as well as the hemodynamic status compared to baseline were also assessed. Methods : Adult patients with a serum total bilirubin level > 10 mg/dL admitted to the Intensive Care Unit were included. Exclusion criteria were hemodynamic instability, postoperative bleeding and platelet count < 20,000/mm3. Results : Seven patients were treated. Serum total bilirubin was significantly reduced at the end of treatment. However, seventy-two hours after the discontinuation of extracorporeal therapy, bilirubin levels returned to baseline levels in four patients. A decrease in platelet count was found during therapy, and platelet transfusion was required in six cases. A significant increase in D-dimer at the end of treatment was detected. HE degree, SOFA and MELD scores remained stable, while a deterioration in hemodynamic status was observed in two cases. Conclusions : Our preliminary findings did not show the possible benefits of CytoSorb ® in rebalancing clinical and laboratory parameters in patients with HD after LT or EHR.

Intensive Care Unit (ICU)-Acquired Weakness (ICU-AW) is a generalized muscle weakness that is clinically detected in critical patients and has no plausible etiology other than critical illness. ICU-AW is uncommon in patients undergoing orthotopic liver transplantation (OLT). Our report sheds light on the highest number of ICU-AW cases observed in a single center on OLT patients with early allograft dysfunction. Out of 282 patients who underwent OLT from January 2015 to June 2023, 7 (2.5%) developed generalized muscle weakness in the ICU and underwent neurophysiological investigations. The neurologic examination showed preserved extraocular, flaccid quadriplegia with the absence of deep tendon reflexes in all patients. Neurophysiological studies, including electromyography and nerve conduction studies, showed abnormalities with fibrillation potentials and the rapid recruitment of small polyphasic motor units in the examined muscles, as well as a reduced amplitude of the compound muscle action potential and sensory nerve action potential, with an absence of demyelinating features. Pre-transplant clinical status was critical in all patients. During ICU stay, early allograft dysfunction, acute kidney injury, prolonged mechanical ventilation, sepsis, hyperglycemia, and high blood transfusions were observed in all patients. Two patients were retransplanted. Five patients were alive at 90 days; two patients died. In non-cooperative OLT patients, neurophysiological investigations are essential for the diagnosis of ICU-AW. In this setting, the high number of red blood cell transfusions is a potential risk factor for ICU-AW.

Competing Interests: All authors declare no competing financial or personal interests.

High End-Surgery Arterial Lactate Concentration (ES-ALC) predicts poor outcome after hepatectomy. The aim of this study was to identify intraoperative hemodynamic parameters predicting high ES-ALC during elective liver resection. Patients who underwent liver resection between 2017 and 2018, under FloTrac/EV1000TM hemodynamic monitoring, were included. The ES-ALC cutoff best predicting severe postoperative complications was identified. Association between high ES-ALC and preoperative and intraoperative variables was assessed. 108 patients were included; 90-day mortality was 0.9% and severe morbidity 14.8%. ES-ALC cutoff best discriminating severe complications was 5.05 mmol/L. Patients with ES-ALC > 5.0 mmol/L had a relative risk of severe complications of 2.8% (p = 0.004). High ES-ALC patients had longer surgery and ischemia duration, larger blood losses and higher requirements of fluids and blood transfusions. During surgery, hemoglobin concentration and oxygen delivery (DO2) decreased more significantly in patients with high ES-ALC, although they had similar values of stroke volume and cardiac output to those of other patients. At multivariate analysis, surgery duration and lowest recorded DO2 value were the strongest predictors of high ES-ALC. ES-ALC > 5.0 mmol/L in elective liver resection predicts postoperative morbidity and is essentially driven by the impaired DO2. Timely correction of blood losses might prevent the ES-ALC increase.

Background: Dengue is a mosquito-borne viral infection with increasing global prevalence. It is endemic in more than 100 countries, with a heavy burden in Asia. Ultrasound findings including gallbladder wall thickening, ascites, and pleural effusions secondary to plasma leakage have been described in dengue. We aimed to determine if the presence of point-of-care ultrasound findings early in suspected dengue could predict clinical worsening in ambulatory pediatric patients., Methods: We did a prospective, single-blinded, observational cohort study at a children's hospital in Siem Reap, Cambodia during periods of dengue outbreak. Ambulatory patients were screened and children ages > 3 month and ≤ 16 years with suspected acute, non-severe dengue were enrolled. Subjects had chest and abdominal ultrasound exams. Independently, subjects were evaluated by a blinded physician who determined a treatment plan as per usual practice. Follow-up was conducted 7-10 days after the initial visit. Analysis of ultrasound findings was performed to determine their relationship with outcome measures including need for unplanned hospital visits or admissions., Findings: A total of 2,186 children were screened during periods of national dengue outbreak in Cambodia in consecutive years 2018-2019, and 253 children met eligibility criteria. Results showed patients with gallbladder wall thickening (> 3·0 mm) who were discharged had a significantly more likely need for unplanned visit or hospitalization than those with normal gallbladder wall, 67% (95% CI 44 - 84) versus 17% (95% CI 12 - 24), p < 0.0001. Subjects with any abnormal ultrasound finding were more likely to be directly admitted versus discharged upon initial presentation, 62·2% (95% CI 46.1 - 76.0) versus 19.5% (95% CI 14.8 - 25.4), p < 0.0001., Interpretation: Point-of-care ultrasound findings, particularly gallbladder wall thickening, in suspected early dengue can help predict disease progression in ambulatory patients. Ultrasound has potential to help guide management of suspected dengue patients and resource management during periods of dengue outbreak., Funding: Society for Academic Emergency Medicine Foundation., Competing Interests: We declare no competing interests., (© 2021 The Author(s).)

Objectives: Pre-pause imaging during cardiopulmonary resuscitation (CPR) involves the acquisition of poor-quality, brief images immediately prior to stopping CPR to allow shorter, better-quality images during the pause. We hypothesize that pre-pause imaging is associated with a decrease in CPR pause length and shorter image acquisition time., Methods: Prospective, interventional cohort study enrolling out-of-hospital (OOH) cardiac arrest patients. Pre-pause imaging involves pre-localizing of the approximate sonographic window during CPR to support subsequent fine tuning when CPR pauses. Physicians were educated on pre-pause imaging and data was recorded prior- and post- introduction of pre-pause imaging into American cardiac life support (ACLS). Timing of CPR pauses and identification of interventions and events during pause were recorded (e.g., intubation, defibrillation, multiple cardiac ultrasounds). Ultrasound (US) images were reviewed for image quality using a 5-point scale. Primary outcome was length of CPR pause with and without pre-pause imaging. Secondary outcome included US length., Results: One hundred and forty five subjects presenting after OOH cardiac arrest were enrolled over 13 months, 70 during the baseline period prior to pre-pause imaging and 75 after pre-pause imaging was integrated into ACLS. Pre-pause imaging decreased CPR pause length from 28.3 s (95%CI 25.1-31.5) to 12.8 s (95%CI 11.9-13.7). US image acquisition time decreased with pre-pause imaging from 20.4 (95%CI 18.0-22.7) to 11.0 s (95%CI 10.1-11.8). US image quality was unchanged despite the decrease in image acquisition time. (3.0 (95%CI 2.8-3.2) vs 2.7 (95%CI 2.5-2.9)). Multivariate modeling showed that ultrasound did not prolong CPR pause length., Conclusion: Pre-pause imaging was associated with significant decrease in CPR pause length and US image acquisition time. Pre-pause imaging should be encouraged for any clinicians who use ultrasound during ACLS., Competing Interests: None declared., (© 2021 The Authors.)

Objective: Research into echocardiography (echo) during cardiac arrest has suffered from methodological flaws that limit aggregation of findings. We developed and validated a novel image rating scale for qualitative analysis of echo images obtained during resuscitation., Methods: A novel 5-point ordinal rating scale was developed and validated using recorded echo images from 145 consecutive cardiac arrest patients. Recorded echo images were reviewed in a blinded fashion by investigators experienced in cardiac arrest echo, and image quality was rated using this scale. Cardiac activity was subsequently classified as no activity, disorganized activity and organized activity. The primary outcome was inter-rater agreement using the image quality rating scale. Secondary outcome was the qualitative evaluation of the type of cardiac activity., Results: A total of 235 ultrasounds were analyzed by study investigators using the image quality rating scale. The overall image quality agreement between reviewers using the scale was good with a weighted kappa of 0.65. Agreement for image quality in subxyphoid images was greater than in parasternal images (0.65-0.52). Echo analysis of cardiac activity showed no activity (33%), disorganized activity (18%), and organized activity (49%). Agreement was great for presence or absence of "cardiac activity" and "organized cardiac activity" with a kappa of 0.84 and 0.78., Conclusions: A novel image quality rating scale for echo during cardiac arrest demonstrates substantial agreement between reviewers. Agreement regarding the presence or absence, as well as the organization of cardiac activity was substantial., Competing Interests: None., (© 2021 The Authors.)

Background: (1,3)-β-D-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis., Methods: This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-D-glucan was negative ((1,3)-β-D-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-D-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment., Results: We randomized 108 patients into the (1,3)-β-D-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1-3] in the (1,3)-β-D-glucan group vs. 10 days [6-13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94-8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-D-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-D-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23)., Conclusions: In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-D-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population., Trial Registration: ClinicalTrials.gov, NCT03117439 , retrospectively registered on 18 April 2017.

Background: High-flow nasal cannula (HFNC) is a key component of oxygen therapy and has largely been used in patients with acute respiratory failure. We conducted a matched controlled study with the aim to compare the preventive use of oxygen therapy delivered by HFNC versus via air-entrainment mask (standard O 2 ) after extubation in adult subjects with liver transplantation for reducing postextubation hypoxemia., Methods: Twenty-nine subjects with liver transplantation who received HFNC after extubation (HFNC group) were matched 1:1 with 29 controls (standard O 2 group) chosen from an historical group of 90 subjects admitted to the ICU during the previous 36 months. The primary outcome of the study was the incidence of hypoxemia at 1 h and 24 h after extubation. Secondary outcomes were the rate of weaning failure, ICU length of stay, and 28-d mortality., Results: The incidence of hypoxemia was not significantly different between the HFNC and standard O 2 groups at 1 h and 24 h after extubation. In the HFNC group, there was a trend toward a lower rate of weaning failure compared with the standard O 2 group. ICU length of stay and 28-d mortality were similar in both groups., Conclusions: Early application of HFNC in the subjects with liver transplantation did not reduce the incidence of hypoxemia after extubation compared with standard O 2 and did not modify the incidence of weaning failure, ICU length of stay, and 28-d mortality in this high-risk population of subjects. (ClinicalTrials.gov registration NCT03441854.)., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2020 by Daedalus Enterprises.)

Introduction: Access to high-quality emergency care in low- and middle-income countries (LMIC) is lacking. Many countries utilise a strategy known as "task-shifting" where skills and responsibilities are distributed in novel ways among healthcare personnel. Point-of-care ultrasound (POCUS) has the potential to significantly improve emergency care in LMICs., Methods: POCUS was incorporated into a training program for a ten-person cohort of non-physician Emergency Care Providers (ECPs) in rural Uganda. We performed a prospective observational evaluation on the impact of a remote, rapid review of POCUS studies on the primary objective of ECP ultrasound quality and secondary objective of ultrasound utilisation. The study was divided into four phases over 11 months: an initial in-person training month, two middle month blocks where ECPs performed ultrasounds independently without remote electronic feedback, and the final months when ECPs performed ultrasounds independently with remote electronic feedback. Quality was assessed on a previously published eight-point ordinal scale by a U.S.-based expert sonographer and rapid standardised feedback was given to ECPs by local staff. Sensitivity and specificity of ultrasound exam findings for the Focused Assessment with Sonography for Trauma (FAST) was calculated., Results: Over the study duration, 1153 ultrasound studies were reviewed. Average imaging frequency per ECP dropped 61% after the initial in-person training month ( p  = 0.01) when ECPs performed ultrasound independently, but rebounded once electronic feedback was initiated ( p  = 0.001), with an improvement in quality from 3.82 (95% CI, 3.32-4.32) to 4.68 (95% CI, 4.35-5.01) on an eight-point scale. The sensitivity and specificity of FAST exam during the initial training period was 77.8 (95% CI, 59.2-83.0) and 98.5 (95% CI, 93.3-99.9), respectively. Sensitivity improved 88% compared to independent, non-feedback months whereas specificity was unchanged., Conclusions: Remotely delivered quality assurance feedback is an effective educational tool to enhance provider skill and foster continued and sustainable use of ultrasound in LMICs., Competing Interests: Grant funding for investigator initiated research: BMT, DLP, MB report grant money to UMass Memorial Emergency Department to conduct research conceived and written by MBT and MB from the UMass Medical School Office of Global Health. The authors declare no conflicts of interest.

Background: Postoperative respiratory failure (PRF, namely mechanical ventilation >48 hours) significantly affects morbidity and mortality in liver transplantation (LTx). Previous studies analyzed only one or two categories of PRF risk factors (preoperative, intraoperative or postoperative ones). The aims of this study were to identify PRF predictors, to assess the length of stay (LoS) in ICU and the 90-day survival according to the PRF in LTx patients., Methods: Two classification approaches were used: systematic classification (recipient-related preoperative factors; intraoperative factors; logistic factors; donor factors; postoperative ICU factors; postoperative surgical factors) and patient/organ classification (patient-related general factors; native-liver factors; new-liver factors; kidney factors; heart factors; brain factors; lung factors). Two hundred adult non-acute patients were included. Missing analysis was performed. The competitive role of each factor was assessed., Results: PRF occurred in 36.0% of cases. Among 28 significant PRF predictors at univariate analysis, 6 were excluded because of collinearity, 22 were investigated by ROC curves and by logistic regression analysis. Recipient age (OR = 1.05; p = 0.010), female sex (OR = 2.75; p = 0.018), Model for End-Stage Liver Disease (MELD, OR = 1.09; p<0.001), restrictive lung pattern (OR = 2.49; p = 0.027), intraoperative veno-venous bypass (VVBP, OR = 3.03; p = 0.008), pre-extubation PaCO2 (OR = 1.11; p = 0.003) and Model for Early Allograft Function (MEAF, OR = 1.37; p<0.001) resulted independent PRF risk factors. As compared to patients without PRF, the PRF-group had longer LoS (10 days IQR 7-18 versus 5 days IQR 4-7, respectively; p<0.001) and lower day-90 survival (86.0% versus 97.6% respectively, p<0.001)., Conclusion: In conclusion, MELD, restrictive lung pattern, surgical complexity as captured by VVBP, pre-extubation PaCO2 and MEAF are the main predictors of PRF in non-acute LTx patients., Competing Interests: The authors have declared that no competing interests exist.

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes, grouped into seven different classes, which catalyze the reaction of CO 2 hydration to bicarbonate and protons. All of the fifteen human isoforms reported to date belong to the α-class and contain zinc as a cofactor. The structure of human Zn,Cu-CA II has been solved which contains a copper ion bound at its N-terminal, coordinated to His4 and His64. In the active site a dioxygen molecule is coordinated to the zinc ion. Since dioxygen is a rather unexpected CA ligand, molecular dynamics (MD) simulations were performed which suggested a superoxide character of the zinc bound O 2 .

Hydrogen bonds are key interactions determining protein-ligand binding affinity and therefore fundamental to any biological process. Unfortunately, explicit structural information about hydrogen positions and thus H-bonds in protein-ligand complexes is extremely rare and similarly the important role of water during binding remains poorly understood. Here, we report on neutron structures of trypsin determined at very high resolutions ≤1.5 Å in uncomplexed and inhibited state complemented by X-ray and thermodynamic data and computer simulations. Our structures show the precise geometry of H-bonds between protein and the inhibitors N-amidinopiperidine and benzamidine along with the dynamics of the residual solvation pattern. Prior to binding, the ligand-free binding pocket is occupied by water molecules characterized by a paucity of H-bonds and high mobility resulting in an imperfect hydration of the critical residue Asp189. This phenomenon likely constitutes a key factor fueling ligand binding via water displacement and helps improving our current view on water influencing protein-ligand recognition.

Objective: Ultrasound (US) has been shown to be effective at identifying a pneumothorax (PTX); however, the additional value of adding multiple views has not been studied. Single- and four-view protocols have both been described in the literature. The objective of this study was to compare the diagnostic accuracy of single-view versus four-view lung US to detect clinically significant PTX in trauma patients., Methods: This was a randomized, prospective trial on trauma patients. Adult patients with acute traumatic injury undergoing computed tomography (CT) scan of the chest were eligible for enrollment. Patients were randomized to a single view or four views of each hemithorax prior to any imaging. USs were performed and interpreted by credentialed physicians using a 7.5-Mhz linear array transducer on a portable US machine with digital clips recorded for later review. Attending radiologist interpretation of the chest CT was reviewed for presence or absence of PTX with descriptions of small foci of air or minimal PTX categorized as clinically insignificant., Results: A total of 260 patients were enrolled over a 2-year period. A total of 139 patients received a single view of each chest wall and 121 patients received four views. There were a total of 49 patients that had a PTX (19%), and 29 of these were clinically significant (11%). In diagnosis of any PTX, both single-view and four-view techniques showed poor sensitivity (54.2 and 68%) but high specificity (99 and 98%). For clinically significant PTX, single-view US demonstrated a sensitivity of 93% (95% confidence interval [CI] = 64.1% to 99.6%) and a specificity of 99.2% (95% CI = 95.5% to 99.9%), with sensitivity of 93.3% (95% CI = 66% to 99.7%) and specificity of 98% (95% CI = 92.1% to 99.7%) for four views., Conclusions: Single-view and four-view chest wall USs demonstrate comparable sensitivity and specificity for PTX. The additional time to obtain four views should be weighed against the absence of additional diagnostic yield over a single view when using US to identify a clinically significant PTX., (© 2016 by the Society for Academic Emergency Medicine.)

Trans-lesion synthesis polymerases, like DNA Polymerase-η (Pol-η), are essential for cell survival. Pol-η bypasses ultraviolet-induced DNA damages via a two-metal-ion mechanism that assures DNA strand elongation, with formation of the leaving group pyrophosphate (PPi). Recent structural and kinetics studies have shown that Pol-η function depends on the highly flexible and conserved Arg61 and, intriguingly, on a transient third ion resolved at the catalytic site, as lately observed in other nucleic acid-processing metalloenzymes. How these conserved structural features facilitate DNA replication, however, is still poorly understood. Through extended molecular dynamics and free energy simulations, we unravel a highly cooperative and dynamic mechanism for DNA elongation and repair, which is here described by an equilibrium ensemble of structures that connect the reactants to the products in Pol-η catalysis. We reveal that specific conformations of Arg61 help facilitate the recruitment of the incoming base and favor the proper formation of a pre-reactive complex in Pol-η for efficient DNA editing. Also, we show that a third transient metal ion, which acts concertedly with Arg61, serves as an exit shuttle for the leaving PPi. Finally, we discuss how this effective and cooperative mechanism for DNA repair may be shared by other DNA-repairing polymerases., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Drug discovery is expensive and high-risk. Its main reasons of failure are lack of efficacy and toxicity of a drug candidate. Binding affinity for the biological target has been usually considered one of the most relevant figures of merit to judge a drug candidate along with bioavailability, selectivity and metabolic properties, which could depend on off-target interactions. Nevertheless, affinity does not always satisfactorily correlate with in vivo drug efficacy. It is indeed becoming increasingly evident that the time a drug spends in contact with its target (aka residence time) can be a more reliable figure of merit. Experimental kinetic measurements are operatively limited by the cost and the time needed to synthesize compounds to be tested, to express and purify the target, and to setup the assays. We present here a simple and efficient molecular-dynamics-based computational approach to prioritize compounds according to their residence time. We devised a multiple-replica scaled molecular dynamics protocol with suitably defined harmonic restraints to accelerate the unbinding events while preserving the native fold. Ligands are ranked according to the mean observed scaled unbinding time. The approach, trivially parallel and easily implementable, was validated against experimental information available on biological systems of pharmacological relevance.

Background: Ultrasound measurement of dynamic changes in inferior vena cava (IVC) diameter can be used to assess intravascular volume status in critically ill patients, but published studies vary in accuracy as well as recommended diagnostic cutoffs. Part of this variability may be related to movements of the vessel relative to the transducer during the respiratory cycle which results in unintended comparison of different points of the IVC at end expiration and inspiration, possibly introducing error related to variations in normal anatomy. The objective of this study was to quantify both craniocaudal and mediolateral movements of the IVC as well as the vessel's axis of collapse during respirophasic ultrasound imaging., Methods: Patients were enrolled from a single urban academic emergency department with ultrasound examinations performed by sonographers experienced in IVC ultrasound. The IVC was imaged from the level of the diaphragm along its entire course to its bifurcation with diameter measurements and respiratory collapse measured at a single point inferior to the confluence of the hepatic veins. While imaging the vessel in its long axis, movement in a craniocaudal direction during respiration was measured by tracking the movement of a fixed point across the field of view. Likewise, imaging the short axis of the IVC allowed for measurement of mediolateral displacement as well as the vessel's angle of collapse relative to vertical., Results: Seventy patients were enrolled over a 6-month period. The average diameter of the IVC was 13.8 mm (95% CI 8.41 to 19.2 mm), with a mean respiratory collapse of 34.8% (95% CI 19.5% to 50.2%). Movement of the vessel relative to the transducer occurred in both mediolateral and craniocaudal directions. Movement was greater in the craniocaudal direction at 21.7 mm compared to the mediolateral movement at 3.9 mm (p < 0.001). Angle of collapse assessed in the transverse plane averaged 115° (95% CI 112° to 118°)., Conclusions: Movement of the IVC occurs in both mediolateral and craniocaudal directions during respirophasic ultrasound imaging. Further, collapse of the vessel occurs not at true vertical (90°) but 25° off this axis. Technical approach to IVC assessment needs to be tailored to account for these factors.

Background: Therapies exist for acute organophosphate (OP) exposure but mortality rates remain high (10% to 20%). Currently, treatment focuses on reversing the resultant cholinergic excess effects through the use of atropine. Intralipid fat emulsion (IFE) has been used to treat lipophilic drug ingestions and theoretically would be beneficial for some OP agents., Objectives: The hypothesis was that IFE would decrease the acute respiratory depressant effects following lethal OP exposure using a lipophilic OP agent (parathion)., Methods: The authors used a previously validated animal model of OP poisoning with detailed physiologic respiratory recordings. The model consisted of Wistar rats anesthetized but spontaneously breathing 100% oxygen. Airflow, respiratory rate, tidal volume, mean arterial pressure, and pulse rate were digitally recorded for 120 minutes following OP exposure or until respiratory failure. Three study groups included parathion alone (n = 6), parathion and IFE 5 minutes after poisoning (n = 6), and parathion and IFE 20 minutes after poisoning (n = 6). In all groups, parathion was given as a single oral dose of 54 mg/kg (four times the rat oral 50% population lethal dose [LD(50) ]). Three boluses of IFE (15 mg/kg/min) were given over 3 minutes, 20 minutes apart, starting either 5 or 20 minutes after poisoning. Timing of IFE was based on parathion kinetics. In one study group IFE was initiated 5 minutes after poisoning to coincide with initial absorption of parathion. In another study group IFE was given at 20 minutes to coincide with peak intravenous (IV) parathion concentration. Primary outcome was percentage of animals with apnea. Secondary outcome was time to apnea., Results: Animals exposed to parathion alone demonstrated a steady decline in respiratory rate and tidal volume postexposure, with apnea occurring a mean of 51.6 minutes after poisoning (95% confidence interval [CI] = 35.8 to 53.2 minutes). Animals treated with IFE 5 minutes postexposure demonstrated no difference in mean time to apnea (44.5 minutes vs. 51.6 minutes, p = 0.29) or number of animals with respiratory arrest (100% vs. 100%, p = 1.00). Animals treated with IFE 20 minutes postexposure demonstrated a significantly prolonged mean time to apnea (95.3 minutes vs. 51.6 minutes, p = 0.002), but there was no difference in number of animals with respiratory arrest (100% vs. 66.7%, p = 0.45)., Conclusions: All animals exposed to 4 × LD(50) of oral parathion demonstrate apnea and respiratory arrest. IFE given immediately after oral parathion does not prolong time to apnea. IFE given 20 minutes after oral exposure to parathion decreases the acute effects of the OP and prolongs the time to apnea., (© 2012 by the Society for Academic Emergency Medicine.)

Background: The diagnosis of a superficial abscess is usually obtained through history and physical exam but bedside ultrasound (US) and computerized tomography (CT) are sometimes used to assist in the diagnosis. It is unclear which imaging modality is superior for patients with superficial soft tissue infections. We compared the diagnostic accuracy of CT and US in patients with skin and soft tissue infections., Methods: Patients presenting with a suspected skin abscess that underwent both US and CT imaging were eligible for inclusion. Two physicians blinded to patient characteristics and other imaging results prospectively reviewed the CT and US images for pre-defined image elements, and in circumstances where there was disagreement between these interpretations, a third physician adjudicated the findings. The presence or absence of an abscess cavity was noted on imaging. Imaging detail was summarized using a pre-specified 4-point scale based on the degree of visible detail with higher numbers corresponding to greater detail. The clinical presence of an abscess was defined by surgical evacuation of purulence. Sensitivity and specificity for both CT and US were calculated using Chi square analysis. Comparison between imaging detail was performed using a Student's T-test. Data are presented with (95% confidence intervals) unless otherwise noted., Results: Over an 18 month period 612 patients received a soft tissue bedside ultrasound with 65 of those patients receiving a CT for the same complaint. 30 of these 65 patients had an abscess located in the head and neck (37%), buttock (17%), lower extremity (17%), upper extremity (13%), torso (13%), or hand (3%). US demonstrated a sensitivity and specificity for the diagnosis of abscess of 96.7% (87.0% to 99.4%) and 85.7% (77.4% to 88.0%) respectively. The overall sensitivity and specificity of CT for the diagnosis of an abscess was 76.7% (65.5% to 82.8%) and 91.4% (81.8% to 96.7%) respectively Overall image detail ratings were superior for US compared to CT (3.5 vs 2.3, p = 0.0001)., Conclusion: US is more sensitive then CT, but CT is more specific for superficial soft tissue abscesses. US demonstrated more visible detail within the abscess cavity compared to CT.