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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.

OBJECTIVE: Despite advances in perioperative care, hepatectomy remains associated with morbidity rates of up to 40%. Currently, available nomograms for predicting severe post-hepatectomy complications do not include early postoperative data. This retrospective observational study aimed to determine whether the parameters routinely measured in patients admitted to the Intensive Care Unit (ICU) after hepatectomy could represent risk factors for severe morbidity and to propose a nomogram scoring system to predict severe postoperative complications. PATIENTS AND METHODS: 411 adult patients who underwent elective hepatectomy at a high-volume tertiary care center for hepatic surgery from December 2016 to June 2022 were enrolled. The primary outcome was the assessment of predictors of 30-day severe postoperative complications following hepatectomy, defined as Clavien-Dindo grade 3a or higher. As a secondary outcome, we aimed to develop an easy-to-use scoring system to estimate the risk of severe postoperative complications. RESULTS: Severe complications occurred in 78 patients (19%). The final model included body mass index, preoperative bilirubin level, and ICU data (i.e., pH, lactate clearance, arterial lactate concentration 12 hours after ICU admission, need for packed red blood cell transfusions, and length of stay). Notably, the latter three variables were proven to be independent predictors of the outcomes. The model showed an overall good fit (C-index=0.754, corrected Dxy=0.692). A calibration plot using bootstrap internal validity resampling confirmed the stability of the model (mean absolute error=0.017, root mean square error of approximation=0.00051). CONCLUSIONS: We developed an accurate and practical scoring system based on preoperative and early postoperative data to predict poor outcomes after hepatectomy. Further external validation on larger series could lead to the integration of such a tool in the routine clinical practice to support patients' management and early warning during ICU stay., Graphical Abstract: https://www.europeanreview.org/wp/wp-content/uploads/Graphical-Abstract-NEW-2.pdf.

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.

Aims:  To evaluate the evidence and produce a summary and recommendations for the most common heart and lung applications of point-of-care ultrasound (PoCUS)., Methods:  We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendation were produced, including assignment of levels of evidence (LoE) and grading of the recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement regarding the summary and recommendation for each question (using a 5-point Likert scale), which was approved if a level of agreement of greater than 75 % was reached. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses., Findings and Recommendations:  One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1). The remaining 9 questions achieved broad agreement with one assigned an LoE of 4 and weak GRADE recommendation (question 2), three achieving an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8), and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10)., Conclusion:  These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings., Competing Interests: A number of authors have declared potential conflicts of interest from the past three years:Bøetker, M.T. [royalties received from e-learning platform USabcd.org]; Connolly, J. [honoraria received from Sonosite FujiFilm UK, equipment loans from Canon Healthcare, Terason Ultrasound, EchoNous]; Gargani, L. [honoraria received from GE Healthcare, Philips Healthcare & Caption Health]; Jarman, R.D. [honoraria received from Sonosite FujiFilm UK, equipment loans from Canon Healthcare]; Kim, D. [medical advisor for Clarius Mobile Health]; Liu, R. [honoraria received from Philips Healthcare]; Olusanya, O. [honoraria received from GE Healthcare & Sonosite FujiFilm UK]; Peck, M. [honoraria received from GE Healthcare]., (Thieme. All rights reserved.)

Objective:  To evaluate the evidence and produce a summary and recommendations for the most common heart and lung point-of-care ultrasound (PoCUS)., Methods:  We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendations were produced, including assigning levels of evidence (LoE) and grading of recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement of the summary and recommendation for each question (using a 5-point Likert scale), which was approved in the case of a level of agreement of greater than 75 %. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses., Findings and Recommendations:  One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1), the remaining 9 questions achieved broad agreement with an assigned LoE of 4 and a weak GRADE recommendation (question 2), three achieved an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8) and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10)., Conclusion:  These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings., Competing Interests: A number of authors have declared potential conflicts of interest from the past three years.Bøetker, M.T. [royalties received from e-learning platform USabcd.org];Connolly, J. [honoraria received from Sonosite FujiFilm UK, equipment loans from Canon Healthcare, Terason Ultrasound, EchoNous]; Gargani, L. [honoraria received from GE Healthcare, Philips Healthcare & Caption Health]; Jarman, R.D. [honoraria received from Sonosite FujiFilm UK, equipment loans from Canon Healthcare];Kim, D. [medical advisor for Clarius Mobile Health]; Liu, R. [honoraria received from Philips Healthcare];Olusanya, O. [honoraria received from GE Healthcare & Sonosite FujiFilm UK];Peck, M. [honoraria received from GE Healthcare]., (Thieme. All rights reserved.)

Background: Recent literature suggests viscoelastic test (VET)-guided transfusion management could be associated with reduced blood product administration in patients undergoing liver transplantation., Objectives: To assess the effectiveness of coagulation management guided by VETs compared with conventional coagulation tests (CCTs) in reducing blood product transfusion in patients undergoing liver transplantation., Design: Systematic review and meta-analysis of randomised (RCTs) and nonrandomised clinical trials performed according to PRISMA guidelines. The protocol was previously published (PROSPERO: CRD42021230213)., Data Sources: The Cochrane Central Library, PubMed/MEDLINE, Embase and the Transfusion Evidence Library were searched up to 30 th January 2022., Eligibility Criteria: Setting: operating room. Patients: liver transplantation recipients. Intervention: use of VETs versus CCTs. Main outcome measures: the primary outcome was the mean number of transfused units for each blood product including red blood cells (RBCs), fresh frozen plasma (FFP), platelets (PLTs) and cryoprecipitate. Secondary outcomes included mortality rate, intensive care unit (ICU) and hospital length of stay (LOS)., Results: Seventeen studies ( n  = 5345 patients), 15 observational and two RCTs, were included in this review. There was a mean difference reduction in RBCs [mean difference: -1.40, 95% confidence interval (95% CI), -1.87 to -0.92; P  < 0.001, I2  = 61%) and FFP units (mean difference: -2.98, 95% CI, -4.61 to -1.35; P  =  < 0.001; I2  = 98%) transfused in the VETs group compared with the CCTs one. A greater amount of cryoprecipitate was administered in the VETs group (mean difference: 2.71, 95% CI, 0.84 to 4.58; P  = 0.005; I2  = 91%). There was no significant difference in the mean number of PLT units, mortality, hospital and ICU-LOS., Conclusion: Our meta-analysis demonstrated that VETs implementation was associated with reduced RBC and FFP consumption in liver transplantation patients without effects on mortality and hospital and ICU-LOS. The certainty of evidence ranged from moderate to very low. Further well conducted RCTs are needed to improve the certainty of evidence., (Copyright © 2022 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

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).)

Objective: Liver transplantation (LT) is associated with a significant bleeding and the high transfusion requirements (HTR) negatively affect the outcome of LT patients. Our primary aim was to identify potential predictors of intraoperative transfusion requirements. Secondarily, we investigated, the effect of transfusion requirements on different clinical outcomes, including short-term morbidity and mortality., Patients and Methods: Data collected in 219 adult LT from a deceased donor, grouped according to HTR (defined as the need of 5 or more red blood cell units), were compared., Results: We found that previous portal vein thromboses (p=0.0156), hemoglobin (Hb) (p<0.0001), International Normalized Ratio (INR) (p=0.0010) at transplant and veno-venous by-pass (p=0.0048) independently predicted HTR. HTR was always associated with poorer outcomes, including higher simplified acute physiology II score at Intensive Care Unit admission (p=0.0005), higher rates of pulmonary infections (p=0.0015) and early rejection (p=0.0176), longer requirement of mechanical ventilation, (p<0.0001), more frequent need for hemodialysis after transplantation (p=0.0036), overall survival (p=0.0010) and rate of day-90 survival (p=0.0016)., Conclusions: This study identified specific risk factors for HTR and confirmed the negative impact exerted by HTR on clinical outcomes, including recipient survival. Prospective investigations are worth to assess whether correcting pre-transplant Hb and INR levels may effectively reduce blood product need and improve prognosis.

Purpose: Skin and soft tissue abscesses are commonly treated in emergency departments (ED). The use of bedside ultrasound may improve patient outcomes. The primary objective of this study was to examine the relationship between ultrasound use and risk of treatment failure in ED patients treated for abscesses., Methods: In this multi-center observational study, we reviewed medical records of adult patients evaluated for abscesses. Demographics, infection characteristics, treatments rendered, use of ultrasound (for diagnosis and/or treatment) and follow-up data were collected from electronic medical record review. Treatment failure, the primary outcome, was defined as any surgical intervention after the initial ED visit. Multivariable logistic regression tested whether incision and drainage utilizing ultrasound was associated with reduced treatment failure., Results: We identified 609 patients diagnosed with abscesses over a 22-month period. Of them 75% were treated with incision and drainage, 55% had an ultrasound and 15% failed treatment. Multi-variable analysis demonstrated an 8% probability of failure with ultrasound plus incision and drainage, 14% with blind incision and drainage and 25% without incision and drainage. Individuals with incision and drainage performed were 50% less likely to fail treatment (RR 0.53, 95%CI 0.35-0.81) and 70% less likely to fail treatment (RR 0.30, 95%CI 0.18-0.51) with ultrasound and incision and drainage., Conclusions: The use of ultrasound in diagnosing and or/treating patients with abscesses in the ED is associated with decreased treatment failure risk when utilized with incision and drainage. Consideration of ultrasound use in other studies which assess treatment methods in relation to patient outcomes may be warranted., (© 2021. The Author(s), under exclusive licence to Canadian Association of Emergency Physicians (CAEP)/ Association Canadienne de Médecine d'Urgence (ACMU).)

Background/objectives: We investigated whether behavioral precautions adopted during Coronavirus disease (COVID-19) pandemic also influenced the spreading and multidrug resistance (MDR) of ESKAPEEc (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii [AB], Pseudomonas aeruginosa, Enterobacter spp and Escherichia Coli, [EC]) among Intensive Care Unit (ICU) patients., Subjects/methods: We performed a single-center retrospective study in adult patients admitted to our COVID-19-free surgical ICU. Only patients staying in ICU for more than 48 hours were included. The ESKAPEEc infections recorded during the COVID-19 period (June 1, 2020 - February 28, 2021) and in the corresponding pre-pandemic period (June 1, 2019 - February 28, 2020) were compared. An interrupted time series analysis was performed to rule out possible confounders., Results: Overall, 173 patients in the COVID-19 period and 132 in the pre-COVID-19 period were investigated. The ESKAPEEc infections were documented in 23 (13.3%) and 35 (26.5%) patients in the pandemic and the pre-pandemic periods, respectively (p = 0.005). Demographics, diagnosis, comorbidities, type of surgery, Simplified Acute Physiology Score II, length of mechanical ventilation, hospital and ICU length of stay, ICU death rate, and 28-day hospital mortality were similar in the two groups. In comparison with the pre-pandemic period, no AB was recorded during COVID-19 period, (p = 0.017), while extended-spectrum beta-lactamase-producing EC infections significantly decreased (p = 0.017). Overall, the ESKAPEEc isolates during pandemic less frequently exhibited multidrug-resistant (p = 0.014)., Conclusions: These findings suggest that a robust adherence to hygiene measures together with human contact restrictions in a COVID-19 free ICU might also restrain the transmission of ESKAPEEc pathogens., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: To measure prevalence of discordance between electrical activity recorded by electrocardiography (ECG) and myocardial activity visualized by echocardiography (echo) in patients presenting after cardiac arrest and to compare survival outcomes in cohorts defined by ECG and echo., Methods: This is a secondary analysis of a previously published prospective study at twenty hospitals. Patients presenting after out-of-hospital arrest were included. The cardiac electrical activity was defined by ECG and contemporaneous myocardial activity was defined by bedside echo. Myocardial activity by echo was classified as myocardial asystole--the absence of myocardial movement, pulseless myocardial activity (PMA)--visible myocardial movement but no pulse, and myocardial fibrillation--visualized fibrillation. Primary outcome was the prevalence of discordance between electrical activity and myocardial activity., Results: 793 patients and 1943 pauses in CPR were included. 28.6% of CPR pauses demonstrated a difference in electrical activity (ECG) and myocardial activity (echo), 5.0% with asystole (ECG) and PMA (echo), and 22.1% with PEA (ECG) and myocardial asystole (echo). Twenty-five percent of the 32 pauses in CPR with a shockable rhythm by echo demonstrated a non-shockable rhythm by ECG and were not defibrillated. Survival for patients with PMA (echo) was 29.1% (95%CI-23.9-34.9) compared to those with PEA (ECG) (21.4%, 95%CI-17.7-25.6)., Conclusion: Patients in cardiac arrest commonly demonstrate different electrical (ECG) and myocardial activity (echo). Further research is needed to better define cardiac activity during cardiac arrest and to explore outcome between groups defined by electrical and myocardial activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Several prospective studies have demonstrated that the echocardiographic detection of any myocardial activity during PEA is strongly associated with higher rates of return of spontaneous circulation (ROSC). We hypothesized that PEA represents a spectrum of disease in which not only the presence of myocardial activity, but more specifically that the degree of left ventricular (LV) function would be a predictor of outcomes. The purpose of this study was to retrospectively assess the association between LV function and outcomes in patients with OHCA., Materials and Methods: Using prospectively obtained data from an observational cohort of patients receiving focused echocardiography during cardiopulmonary resuscitation (CPR) in the Emergency Department (ED) setting, we analyzed 312 consecutive subjects with available echocardiography images with initial rhythm of PEA. We used left ventricular systolic fractional shortening (LVFS), a unidimensional echocardiographic parameter to perform the quantification of LV function during PEA. Regression analyses were performed independently to evaluate for relationships between LVFS and a primary outcome of ROSC and secondary outcome of survival to hospital admission. We analyzed LVFS both as a continuous variable and as a categorial variable using the quartiles and the median to perform multiple different comparisons and to illustrate the relationship of LVFS and outcomes of interest. We performed survival analysis using Cox proportional hazards model to evaluate the hazard corresponding to length of resuscitation., Results: We found a positive association between LVFS and the primary outcome of ROSC (OR 1.04, 95%CI 1.01-1.08), but not with the secondary outcome of survival to hospital admission (OR 1.02, 95%CI 0.96-1.08). Given that the relationship was not linear and that we observed a threshold effect in the relationship between LVFS and outcomes, we performed an analysis using quartiles of LVFS. The predicted probability of ROSC was 75% for LVFS between 23.4-96% (fourth quartile) compared to 47% for LVFS between 0-4.7% (first quartile). The hazard of not achieving ROSC was significantly greater for subjects with LVFS below the median (13.1%) compared to the subgroup with LVFS greater than 13.1% (p < 0.05), with the separation of the survival curves occurring at approximately 40 min of resuscitation duration., Conclusions: Left ventricular function measured by LVFS is positively correlated with higher probability of ROSC and may be associated with higher chances of survival in patients with PEA arrest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Study Objective: To compare total blood product requirements in liver transplantation (LT) assisted by thromboelastography (TEG) or conventional coagulation tests (CCTs)., Design: Retrospective observational study., Setting: A tertiary care referral center for LT., Patients: Adult patients undergoing LT from deceased donor., Intervention: Hemostasis was monitored by TEG or CCTs and corresponding transfusion algorithms were adopted., Measurements: Number and types of blood products (red blood cells, RBC; fresh-frozen plasma, FFP; platelets, PLT) transfused from the beginning of surgery until the admission to the intensive care unit., Methods: We compared data retrospectively collected in 226 LTs, grouped according to the type of hemostasis monitoring (90 with TEG and 136 with CCTs, respectively). Confounding variables affecting transfusion needs (recipient age, sex, previous hepatocellular carcinoma surgery, Model for End Stage Liver Disease - MELD, baseline hemoglobin, fibrinogen, creatinine, veno-venous by pass, and trans-jugular intrahepatic portosystemic shunt) were managed by propensity score match (PSM)., Main Results: The preliminary analysis showed that patients in the TEG group received fewer total blood products (RBC + FFP + PLT; p = 0.001, FFP (p = 0.001), and RBC (p = 0.001). After PSM, 89 CCT patients were selected and matched to the 90 TEG patients. CCT and TEG matched patients received similar amount of total blood products. In a subgroup of 39 patients in the top MELD quartile (MELD ≥25), the TEG use resulted in lower consumption of FFP units and total blood products. Nevertheless, due to the low number of patients, any meaningful conclusion could be achieved in this subgroup., Conclusions: In our experience, TEG-guided transfusion in LT does not reduce the intraoperative blood product consumption. Further studies are warranted to assess an advantage for TEG in either the entire LT population or the high-MELD subgroup of patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dynamical properties are of great importance in determining the behavior of synthetic and natural molecules, but capturing them by computational methods is a nontrivial task. Very often the time scales of the relevant phenomena are far beyond the typical time windows accessible by classical Molecular Dynamics (MD) simulations, currently limited to the order of microseconds on standard laboratory workstations. On the other hand, biased and accelerated simulations allow for fast and thorough exploration of the molecular conformational space, but they lose the dynamic information. The problem of recovering dynamics from biased/accelerated simulations is a very active field of research, but no totally robust/reliable solutions have been given yet. In this paper it is shown how the Smoluchowski equation, in the framework of Diffusion Theory (DT), can be used to bridge this gap, and dynamical properties, in the form of time correlation functions (TCFs), can be extracted also from such kind of simulations. DT is first extended (EDT) to express the mobility tensors entering the Smoluchowski operator in terms of a recently introduced unified and regularized Rotne-Prager-Yamakawa approximation, [P. J. Zuk, E. Wajnryb, K. A. Mizerski, P. Szymczak, J. Fluid. Mech. 2014, 741, R5, 1-13] also involving mixed rotation-translation contributions, and rotation-rotation terms beside the classical translation-translation ones, so far used in DT. Then, the method is applied to recover the dynamics of a nontrivial example of a peptide in explicit water from the first 200 ns of a Replica Exchange Molecular Dynamics simulation, which is a popular computational method that destroys the long time dynamics. EDT dynamics were found to favorably compare against those coming from a standard MD simulation of the same system, requiring a time window of 30 μs to converge. This result shows that EDT is a tool of practical value to recover the long time dynamics of systems in diffusive regimes from biased/accelerated simulations, to be exploited in those cases when direct evaluation by standard MD is unfeasible., (© 2020 Wiley Periodicals LLC.)

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: Early increase of hepatic artery resistive index (HARI) is frequently observed after liver transplant (LTx)., Aim: We aimed to investigate contributing factors and prognostic relevance of high HARI after LTx from deceased donor., Methods: We conducted a retrospective analysis of prospectively collected data from January 2017 and February 2019. According to the Duplex Doppler HARI values (3 d post-operative day), patients were grouped in normal (0.55-0.80) and high (>0.80-1) HARI groups., Results: Among 81 LTx, 36 had a high HARI and 45 a normal HARI. Patients developing high HARI were older, exhibited lower platelet, hemoglobin, platelet count/spleen diameter ratio, higher serum creatinine, and a more pronounced spleen enlargement (median values 170 versus 120 mm). At multivariate analysis, PLT/spleen diameter ratio (OR 0.994, p < 0.001) creatinine levels (OR 2.418, p = 0.029), and recipient age (OR 1.157, p = 0.004) significantly predicted the occurrence of high HARI. Patients with high or normal HARI had similar vascular complications, rejection rate and 90-day mortality. In most cases, HARI recovered to normal without any clinical effect., Conclusions: HARI rises in presence of several surrogate markers of portal hypertension. The increase is mostly transitory, and it may result from the hepatic artery spasm due to the high portal blood flow., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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.

We investigated pseudo-cubic Cu 2- x Te nanosheets using electron diffraction tomography and high-resolution HAADF-STEM imaging. The structure of this metastable nanomaterial, which has a strong localized surface plasmon resonance in the near-infrared region, was determined ab initio by 3D electron diffraction data recorded in low-dose nanobeam precession mode, using a new generation background-free single-electron detector. The presence of two different, crystallographically defined modulations creates a 3D connected vacancy channel system, which may account for the strong plasmonic response of this material. Moreover, a pervasive rotational twinning is observed for nanosheets as thin as 40 nm, resulting in a tetragonal pseudo-symmetry.

The quest for materials with metal-like properties as alternatives to noble metals is an intense area of research that is set to lead to dramatic improvements in technologies based on plasmonics. Here, we present intermediate band (IB) semiconductor nanocrystals (NCs) as a class of all-dielectric nanomaterials providing quasi-static optical resonances. We show that IB NCs can display a negative permittivity in a broad range of visible wavelengths, enabling a metal-like optical response despite the absence of free carriers in the NC ground state. Using a combination of spectroscopy measurements and ab initio calculations, we hereby provide a theoretical model for both the linear and nonlinear optical properties of chalcopyrite CuFeS 2 NCs, as a case study of IB semiconductor nanomaterials. Our results rationalize the high performance of IB nanomaterials as photothermal agents and suggest the use of IB semiconductors as alternatives to noble metals for technologies based on plasmonic materials.

Objective: Our objective was to determine whether organized or disorganized cardiac activity is associated with increased survival in patients who present in pulseless electrical activity (PEA) treated with either 1) standard advanced cardiac life support (ACLS) medications or 2) other interventions., Methods: This was a secondary analysis of a prospective, multi-center observational study utilizing ultrasound in out-of-hospital or inemergency department PEA arrest. Bedside ultrasound was performed as ACLS protocol started and during pulse checks. Only cases with visible cardiac activity on ultrasound were included in the present analysis. Cardiac activity was categorized as disorganized (agonal twitching) or organized (contractions with changes in ventricular dimensions). Patients were categorized as receiving either standard bolus ACLS medications or alternative medications during the resuscitation (continuous adrenergic agents, thrombolytics, others). The primary outcome was survival to hospital admission. The secondary outcome was return of spontaneous circulation (ROSC). Multivariate modeling was performed to assess association between survival to hospital admission in patients with intravenous adrenergic agents and cardiac activity., Results: In our cohort of 225 patients in PEA cardiac arrest with cardiac activity on ultrasound, the overall survival rate was higher in patients with organized cardiac activity than with disorganized cardiac activity. PEA cardiac arrest patients with organized cardiac activity treated with standard ACLS interventions demonstrated improved survival to hospital admission compared to those with disorganized activity (37.7% (95%CI 24.8-50.2%) versus 17.9% (95%CI 10.9-28%). PEA cardiac arrest patients with organized cardiac activity who received continuous adrenergic agents during the resuscitation and prior to ROSC demonstrated higher survival to hospital admission 45.5% (95%CI 26.9-65.4%) and ROSC 90.9% (95%CI 71.0-98.7%) compared to those with disorganized cardiac activity who received continuous adrenergic agents during the resuscitation 0% (95%CI 0-23.0%) and 47.1% (95%CI 26-69%). Regression analysis demonstrates an association between increased survival in patients receiving intravenous adrenergic agents and organized cardiac activity., Conclusion: Survival in patients following PEA arrest is higher in patients with organized cardiac activity. The initiation of continuous adrenergic agents during PEA was associated with improved survival to hospital admission in patients with organized cardiac activity on bedside ultrasound, but this improvement was not seen in patients in PEA with disorganized cardiac activity. Bedside ultrasound may identify a subset of patients that respond differently to ACLS interventions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Stoichiometric Cu 2 Se nanocrystals were synthesized in either cubic or hexagonal (metastable) crystal structures and used as the host material in cation exchange reactions with Pb 2+ ions. Even if the final product of the exchange, in both cases, was rock-salt PbSe nanocrystals, we show here that the crystal structure of the starting nanocrystals has a strong influence on the exchange pathway. The exposure of cubic Cu 2 Se nanocrystals to Pb 2+ cations led to the initial formation of PbSe unselectively on the overall surface of the host nanocrystals, generating Cu 2 Se@PbSe core@shell nanoheterostructures. The formation of such intermediates was attributed to the low diffusivity of Pb 2+ ions inside the host lattice and to the absence of preferred entry points in cubic Cu 2 Se. On the other hand, in hexagonal Cu 2 Se nanocrystals, the entrance of Pb 2+ ions generated PbSe stripes "sandwiched" in between hexagonal Cu 2 Se domains. These peculiar heterostructures formed as a consequence of the preferential diffusion of Pb 2+ ions through specific (a, b) planes of the hexagonal Cu 2 Se structure, which are characterized by almost empty octahedral sites. Our findings suggest that the morphology of the nanoheterostructures, formed upon partial cation exchange reactions, is intimately connected not only to the NC host material, but also to its crystal structure.

Hydrogen atoms play a key role in protein-ligand recognition. They determine the quality of established H-bonding networks and define the protonation of bound ligands. Structural visualization of H atoms by X-ray crystallography is rarely possible. We used neutron diffraction to determine the positions of the hydrogen atoms in the ligands aniline and 2-aminopyridine bound to the archetypical serine protease trypsin. The resulting structures show the best resolution so far achieved for proteins larger than 100 residues and allow an accurate description of the protonation states and interactions with nearby water molecules. Despite its low pK a of 4.6 and a large distance of 3.6 Å to the charged Asp189 at the bottom of the S1 pocket, the amino group of aniline becomes protonated, whereas in 2-aminopyridine, the pyridine nitrogen picks up the proton although its amino group is 1.6 Å closer to Asp189. Therefore, apart from charge-charge distances, tautomer stability is decisive for the resulting binding poses, an aspect that is pivotal for predicting correct binding., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report a low-temperature colloidal synthesis of single-layer, five-atom-thick, β-In 2 Se 3 nanosheets with lateral sizes tunable from ∼300 to ∼900 nm, using short aminonitriles (dicyandiamide or cyanamide) as shape controlling agents. The phase and the monolayer nature of the nanosheets were ascertained by analyzing the intensity ratio between two diffraction peaks from two-dimensional slabs of the various phases, determined by diffraction simulations. These findings were further backed-up by comparing and fitting the experimental X-ray diffraction pattern with Debye formula simulated patterns and with side-view high-resolution transmission electron microscopy imaging and simulation. The β-In 2 Se 3 nanosheets were found to be indirect band gap semiconductors (E g = 1.55 eV), and single nanosheet photodetectors demonstrated high photoresponsivity and fast response times.

We report the colloidal synthesis of ∼5.5 nm inverse spinel-type oxide Ga 2 FeO 4 (GFO) nanocrystals (NCs) with control over the gallium and iron content. As recently theoretically predicted, some classes of spinel-type oxide materials can be intrinsically doped by means of structural disorder and/or change in stoichiometry. Here we show that, indeed, while stoichiometric Ga 2 FeO 4 NCs are intrinsic small bandgap semiconductors, off-stoichiometric GFO NCs, produced under either Fe-rich or Ga-rich conditions, behave as degenerately doped semiconductors. As a consequence of the generation of free carriers, both Fe-rich and Ga-rich GFO NCs exhibit a localized surface plasmon resonance in the near-infrared at ∼1000 nm, as confirmed by our pump-probe absorption measurements. Noteworthy, the photoelectrochemical characterization of our GFO NCs reveal that the majority carriers are holes in Fe-rich samples, and electrons in Ga-rich ones, highlighting the bipolar nature of this material. The behavior of such off-stoichiometric NCs was explained by our density functional theory calculations as follows: the substitution of Ga 3+ by Fe 2+ ions, occurring in Fe-rich conditions, can generate free holes (p-type doping), while the replacement of Fe 2+ by Ga 3+ cations, taking place in Ga-rich samples, produces free electrons (n-type doping). These findings underscore the potential relevance of spinel-type oxides as p-type transparent conductive oxides and as plasmonic semiconductors.

Herein, we present a new computational approach for analyzing hydration patterns in biomolecular systems. This protocol aims to efficiently identify regions where structural waters may be located and, in the case of protein-ligand binding, where displacing one or more water molecules could be advantageous in terms of affinity and/or residence time. We validated our approach on the adenosine A 2A receptor, a target of significant pharmaceutical relevance. The results of the approach are enriched with an extensive analysis of hydration in A 2A and other members of the A-family of GPCRs using available crystallographic evidence and reviewing existing literature. As per the protein-ligand complex case, we conducted a more detailed study of a series of triazine analogues inhibiting A 2A . The proposed approach provides results in good agreement with existing data and offers interpretability and simple and fast applicability.

Background: Point-of-care ultrasound has been suggested to improve outcomes from advanced cardiac life support (ACLS), but no large studies have explored how it should be incorporated into ACLS. Our aim was to determine whether cardiac activity on ultrasound during ACLS is associated with improved survival., Methods: We conducted a non-randomized, prospective, protocol-driven observational study at 20 hospitals across United States and Canada. Patients presenting with out-of-hospital arrest or in-ED arrest with pulseless electrical activity or asystole were included. An ultrasound was performed at the beginning and end of ACLS. The primary outcome was survival to hospital admission. Secondary outcomes included survival to hospital discharge and return of spontaneous circulation., Findings: 793 patients were enrolled, 208 (26.2%) survived the initial resuscitation, 114 (14.4%) survived to hospital admission, and 13 (1.6%) survived to hospital discharge. Cardiac activity on US was the variable most associated with survival at all time points. On multivariate regression modeling, cardiac activity was associated with increased survival to hospital admission (OR 3.6, 2.2-5.9) and hospital discharge (OR 5.7, 1.5-21.9). No cardiac activity on US was associated with non-survival, but 0.6% (95% CI 0.3-2.3) survived to discharge. Ultrasound identified findings that responded to non-ACLS interventions. Patients with pericardial effusion and pericardiocentesis demonstrated higher survival rates (15.4%) compared to all others (1.3%)., Conclusion: Cardiac activity on ultrasound was the variable most associated with survival following cardiac arrest. Ultrasound during cardiac arrest identifies interventions outside of the standard ACLS algorithm., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

A number of structural factors modulate the activity of Abelson (Abl) tyrosine kinase, whose deregulation is often related to oncogenic processes. First, only the open conformation of the Abl kinase domain's activation loop (A-loop) favors ATP binding to the catalytic cleft. In this regard, the trans-autophosphorylation of the Y412 residue, which is located along the A-loop, favors the stability of the open conformation, in turn enhancing Abl activity. Another key factor for full Abl activity is the formation of active conformations of the catalytic DFG motif in the Abl kinase domain. Furthermore, binding of the SH2 domain to the N-lobe of the Abl kinase was recently demonstrated to have a long-range allosteric effect on the stabilization of the A-loop open state. Intriguingly, these distinct structural factors imply a complex signal transmission network for controlling the A-loop's flexibility and conformational preference for optimal Abl function. However, the exact dynamical features of this signal transmission network structure remain unclear. Here, we report on microsecond-long molecular dynamics coupled with enhanced sampling simulations of multiple Abl model systems, in the presence or absence of the SH2 domain and with the DFG motif flipped in two ways (in or out conformation). Through comparative analysis, our simulations augment the interpretation of the existing Abl experimental data, revealing a dynamical network of interactions that interconnect SH2 domain binding with A-loop plasticity and Y412 autophosphorylation in Abl. This signaling network engages the DFG motif and, importantly, other conserved structural elements of the kinase domain, namely, the EPK-ELK H-bond network and the HRD motif. Our results show that the signal propagation for modulating the A-loop spatial localization is highly dependent on the HRD motif conformation, which thus acts as the central hub of this (allosteric) signaling network controlling Abl activation and function.

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.)

The structural and compositional stabilities of two-dimensional (2D) Bi2Te3 and Bi2Se3 nanocrystals, produced by both colloidal synthesis and by liquid phase exfoliation, were studied by in situ transmission electron microscopy (TEM) during annealing at temperatures between 350 and 500 °C. The sublimation process induced by annealing is structurally and chemically anisotropic and takes place through the preferential dismantling of the prismatic {011̅0} type planes, and through the preferential sublimation of Te (or Se). The observed anisotropic sublimation is independent of the method of nanocrystal's synthesis, their morphology, or the presence of surfactant molecules on the nanocrystals surface. A thickness-dependent depression in the sublimation point has been observed with nanocrystals thinner than about 15 nm. The Bi2Se3 nanocrystals were found to sublimate below 280 °C, while the Bi2Te3 ones sublimated at temperatures between 350 and 450 °C, depending on their thickness, under the vacuum conditions in the TEM column. Density functional theory calculations confirm that the sublimation of the prismatic {011̅0} facets is more energetically favorable. Within the level of modeling employed, the sublimation occurs at a rate about 700 times faster than the sublimation of the {0001} planes at the annealing temperatures used in this work. This supports the distinctly anisotropic mechanisms of both sublimation and growth of Bi2Te3 and Bi2Se3 nanocrystals, known to preferentially adopt a 2D morphology. The anisotropic sublimation behavior is in agreement with the intrinsic anisotropy in the surface free energy brought about by the crystal structure of Bi2Te3 or Bi2Se3.

We describe the colloidal hot-injection synthesis of phase-pure nanocrystals (NCs) of a highly abundant mineral, chalcopyrite (CuFeS 2 ). Absorption bands centered at around 480 and 950 nm, spanning almost the entire visible and near-infrared regions, encompass their optical extinction characteristics. These peaks are ascribable to electronic transitions from the valence band (VB) to the empty intermediate band (IB), located in the fundamental gap and mainly composed of Fe 3d orbitals. Laser-irradiation (at 808 nm) of an aqueous suspension of CuFeS 2 NCs exhibited significant heating, with a photothermal conversion efficiency of 49%. Such efficient heating is ascribable to the carrier relaxation within the broad IB band (owing to the indirect VB-IB gap), as corroborated by transient absorption measurements. The intense absorption and high photothermal transduction efficiency (PTE) of these NCs in the so-called biological window (650-900 nm) make them suitable for photothermal therapy as demonstrated by tumor cell annihilation upon laser irradiation. The otherwise harmless nature of these NCs in dark conditions was confirmed by in vitro toxicity tests on two different cell lines. The presence of the deep Fe levels constituting the IB is the origin of such enhanced PTE, which can be used to design other high performing NC photothermal agents.

Cu2-xTe nanocubes were used as starting seeds to access metal telluride nanocrystals by cation exchanges at room temperature. The coordination number of the entering cations was found to play an important role in dictating the reaction pathways. The exchanges with tetrahedrally coordinated cations (i.e., with coordination number 4), such as Cd(2+) or Hg(2+), yielded monocrystalline CdTe or HgTe nanocrystals with Cu2-xTe/CdTe or Cu2-xTe/HgTe Janus-like heterostructures as intermediates. The formation of Janus-like architectures was attributed to the high diffusion rate of the relatively small tetrahedrally coordinated cations, which could rapidly diffuse in the Cu2-xTe NCs and nucleate the CdTe (or HgTe) phase in a preferred region of the host structure. Also, with both Cd(2+) and Hg(2+) ions the exchange led to wurtzite CdTe and HgTe phases rather than the more stable zinc-blende ones, indicating that the anion framework of the starting Cu2-xTe particles could be more easily deformed to match the anion framework of the metastable wurtzite structures. As hexagonal HgTe had never been reported to date, this represents another case of metastable new phases that can only be accessed by cation exchange. On the other hand, the exchanges involving octahedrally coordinated ions (i.e., with coordination number 6), such as Pb(2+) or Sn(2+), yielded rock-salt polycrystalline PbTe or SnTe nanocrystals with Cu2-xTe@PbTe or Cu2-xTe@SnTe core@shell architectures at the early stages of the exchange process. In this case, the octahedrally coordinated ions are probably too large to diffuse easily through the Cu2-xTe structure: their limited diffusion rate restricts their initial reaction to the surface of the nanocrystals, where cation exchange is initiated unselectively, leading to core@shell architectures. Interestingly, these heterostructures were found to be metastable as they evolved to stable Janus-like architectures if annealed at 200 °C under vacuum.

The binding of sulfonamides to human carbonic anhydrase II (hCAII) is a complex and long-debated example of protein-ligand recognition and interaction. In this study, we investigate the para-substituted n-alkyl and hydroxyethylene-benzenesulfonamides, providing a complete reconstruction of their binding pathway to hCAII by means of large-scale molecular dynamics simulations, density functional calculations, surface plasmon resonance (SPR) measurements, and X-ray crystallography experiments. Our analysis shows that the protein-ligand association rate (kon) dramatically increases with the ligand's hydrophobicity, pointing to the existence of a prebinding stage largely stabilized by a favorable packing of the ligand's apolar moieties with the hCAII "hydrophobic wall". The characterization of the binding pathway allows an unprecedented understanding of the structure-kinetic relationship in hCAII/benzenesulfonamide complexes, depicting a paradigmatic scenario for the multistep binding process in protein-ligand systems.

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.)

Alagille syndrome (AS) is an autosomal-dominant, multisystem disorder affecting the liver, heart, eyes, skeleton, and face. The manifestations are predominantly pediatric. Diagnosis is based on findings of a paucity of bile ducts on liver biopsy combined with ≥3 of 5 major clinical criteria. Orthotopic liver transplantation (OLT) is the only option for treating patients who developed liver failure, portal hypertension, severe itching, and xanthomatosis. It is difficult to establish clear criteria for OLT; indications are controversial because of the wide variety of clinical symptoms and the multisystem involvement. Generally, AS-associated liver disease is never an acute illness. We report the case of a 28-year-old woman with AS who underwent urgent OLT for acute liver failure. At 24 months posttransplant, the patient is in good clinical condition and with normal hepatic and renal function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We report on pyramid-shaped wurtzite cadmium selenide (CdSe) nanocrystals (NCs), synthesized by hot injection in the presence of chloride ions as shape-directing agents, exhibiting reversed crystal polarity compared to former reports. Advanced transmission electron microscopy (TEM) techniques (image-corrected high-resolution TEM with exit wave reconstruction and probe-corrected high-angle annular dark field-scanning TEM) unequivocally indicate that the triangular base of the pyramids is the polar (0001̅) facet and their apex points toward the [0001] direction. Density functional theory calculations, based on a simple model of binding of Cl(-) ions to surface Cd atoms, support the experimentally evident higher thermodynamic stability of the (0001̅) facet over the (0001) one conferred by Cl(-) ions. The relative stability of the two polar facets of wurtzite CdSe is reversed compared to previous experimental and computational studies on Cd chalcogenide NCs, in which no Cl-based chemicals were deliberately used in the synthesis or no Cl(-) ions were considered in the binding models. Self-assembly of these pyramids in a peculiar clover-like geometry, triggered by the addition of oleic acid, suggests that the basal (polar) facet has a density and perhaps type of ligands significantly different from the other three facets, since the pyramids interact with each other exclusively via their lateral facets. A superstructure, however with no long-range order, is observed for clovers with their (0001̅) facets roughly facing each other. The CdSe pyramids were also exploited as seeds for CdS pods growth, and the peculiar shape of the derived branched nanostructures clearly arises from the inverted polarity of the seeds.