Knowledge and barriers of out of hospital cardiac arrest bystander intervention and public access automated external defibrillator use in the Northeast of England: a cross-sectional survey study.

Intervention by members of the public during an out of hospital cardiac arrest (OHAC) including resuscitation attempts and accessible automated external defibrillator (AED) has been shown to improve survival. This study aimed to investigate the OHCA and AED knowledge and confidence, and barriers to intervention, of the public of North East England, UK. This study used a face-to-face cross-sectional survey on a public high street in Newcastle, UK. Participants were asked unprompted to explain what they would do when faced with an OHCA collapse. Chi-Square analysis was used to test the association of the independent variables sex and first aid trained on the participants' responses. Of the 421 participants recruited to our study, 82.9% (n = 349) reported that they would know what to do during an OHCA collapse. The most frequent OHCA action mentioned was call 999 (64.1%, n = 270/421) and 58.2% (n = 245/421) of participants reported that they would commence CPR. However, only 14.3% (n = 60/421) of participants spontaneously mentioned that they would locate an AED, while only 4.5% (n = 19/421) recounted that they would apply the AED. Just over half of participants (50.8%, n = 214/421) were first aid trained, with statistically more females (57.3%, n = 126/220) than males (43.9%,  n = 87/198) being first aiders (p = 0.01 χ2 = 7.41). Most participants (80.3%, n = 338/421) knew what an AED was, and 34.7% (n = 326/421) reported that they knew how to use one, however, only 11.9% (n = 50/421) mentioned that they would actually shock a patient. Being first aid trained increased the likelihood of freely recounting actions for OHCA and AED intervention. The most common barrier to helping during an OHCA was lack of knowledge (29.9%, n = 126/421). Although most participants reported they would know what to do during an OHCA and had knowledge of an AED, low numbers of participants spontaneously mentioned specific OHCA and AED actions. Improving public knowledge would help improve the public's confidence of intervening during an OHCA and may improve OHCA survival.

Recent advances in the management of hepatocellular carcinoma.

Liver cancer remains a challenge of global health, being the 4th leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is usually precipitated by chronic viral infections (hepatitis B and C), non-alcoholic steatohepatitis, heavy alcohol use, and other factors which may lead to chronic inflammation and cirrhosis of the liver. There have been significant advances in the systemic treatment options for HCC over the past decades, with several approvals of both immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with preserved liver function. These advances have led to improvement in survival outcomes, with expected survival of greater than 18 months, in those with sensitive tumors, adequate liver function, and those functionally fit to receive sequential therapies. Several ongoing and promising trials are now evaluating combinational strategies with novel systemic agents and combinations of systemic therapy with locoregional therapy. In view of these trials, further advances in the treatment of HCC are foreseen in the near future.

Using Broken Windows Theory as the Backdrop for a Proactive Approach to Threat Identification in Health Care.

OBJECTIVES: Historically, health care has relied on error management techniques to measure and reduce the occurrence of adverse events. This study proposes an alternative approach for identifying and analyzing hazardous events. Whereas previous research has concentrated on investigating individual flow disruptions, we maintain the industry should focus on threat windows, or the accumulation of these disruptions. This methodology, driven by the broken windows theory, allows us to identify process inefficiencies before they manifest and open the door for the occurrence of errors and adverse events. METHODS: Medical human factors researchers observed disruptions during 34 trauma cases at a Level II trauma center. Data were collected during resuscitation and imaging and were classified using a human factors taxonomy: Realizing Improved Patient Care Through Human-Centered Operating Room Design for Threat Window Analysis (RIPCHORD-TWA). RESULTS: Of the 576 total disruptions observed, communication issues were the most prevalent (28%), followed by interruptions and coordination issues (24% each). Issues related to layout (16%), usability (5%), and equipment (2%) comprised the remainder of the observations. Disruptions involving communication issues were more prevalent during resuscitation, whereas coordination problems were observed more frequently during imaging. CONCLUSIONS: Rather than solely investigating errors and adverse events, we propose conceptualizing the accumulation of disruptions in terms of threat windows as a means to analyze potential threats to the integrity of the trauma care system. This approach allows for the improved identification of system weaknesses or threats, affording us the ability to address these inefficiencies and intervene before errors and adverse events may occur.

RNA knockdown by synthetic peptidyl-oligonucleotide ribonucleases: behavior of recognition and cleavage elements under physiological conditions.

Sequence-specific protein-based ribonucleases are not found in nature. Absolute sequence selectivity in RNA cleavage in vivo normally requires multi-component complexes that recruit a guide RNA or DNA for target recognition and a protein-RNA assembly for catalytic functioning (e.g. RNAi molecular machinery, RNase H). Recently discovered peptidyl-oligonucleotide synthetic ribonucleases selectively knock down pathogenic RNAs by irreversible cleavage to offer unprecedented opportunities for control of disease-relevant RNA. Understanding how to increase their potency, selectivity and catalytic turnover will open the translational pathway to successful therapeutics. Yet, very little is known about how these chemical ribonucleases bind, cleave and leave their target. Rational design awaits this understanding in order to control therapy, particularly how to overcome the trade-off between sequence specificity and potency through catalytic turnover. We illuminate this here by characterizing the interactions of these chemical RNases with both complementary and non-complementary RNAs using Tm profiles, fluorescence, UV-visible and NMR spectroscopies. Crucially, the level of counter cations, which are tightly-controlled within cellular compartments, also controlled these interactions. The oligonucleotide component dominated interaction between conjugates and complementary targets in the presence of physiological levels of counter cations (K+), sufficient to prevent repulsion between the complementary nucleic acid strands to allow Watson-Crick hydrogen bonding. In contrast, the positively-charged catalytic peptide interacted poorly with target RNA, when counter cations similarly screened the negatively-charged sugar-phosphate RNA backbones. The peptide only became the key player, when counter cations were insufficient for charge screening; moreover, only under such non-physiological conditions did conjugates form strong complexes with non-complementary RNAs.Communicated by Ramaswamy H. Sarma.

A Data-Driven Approach to Team Training for Nurses in a Level II Trauma Center.

This prospective investigation describes the process of designing a targeted, data-driven team training aimed at reducing identified process inefficiencies or flow disruptions (FDs) that threaten the optimal delivery of trauma care. Trained researchers observed and classified FDs during 34 trauma cases in a Level II trauma center. Multidisciplinary trauma personnel generated interventions to identified issues using the human factors intervention matrix (HFIX). This article focuses on one intervention: a formal trauma nurse training program centered around leadership, teamwork, and communication. The training was well perceived and was found to have a significant impact on participant knowledge of course content; t (65) = -13.92, p ≤ .01. By using hospital-specific data to drive intervention development from multidisciplinary team members, it is possible to develop effective solutions aimed at addressing individual threats.

Proactive Safety Management in Trauma Care: Applying the Human Factors Analysis and Classification System.

INTRODUCTION: This article examines the reliability of the Human Factors Analysis and Classification System (HFACS) for classifying observational human factors data collected prospectively in a trauma resuscitation center. METHODS: Three trained human factors analysts individually categorized 1,137 workflow disruptions identified in a previously collected data set involving 65 observed trauma care cases using the HFACS framework. RESULTS: Results revealed that the framework was substantially reliable overall (κ = 0.680); agreement increased when only the preconditions for unsafe acts were investigated (κ = 0.757). Findings of the analysis also revealed that the preconditions for unsafe acts category was most highly populated (91.95%), consisting mainly of failures involving communication, coordination, and planning. CONCLUSION: This study helps validate the use of HFACS as a tool for classifying observational data in a variety of medical domains. By identifying preconditions for unsafe acts, health care professionals may be able to construct a more robust safety management system that may provide a better understanding of the types of threats that can impact patient safety.

Phase II Study of First-Line Trebananib Plus Sorafenib in Patients with Advanced Hepatocellular Carcinoma.

LESSONS LEARNED: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. BACKGROUND: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). METHODS: Patients with HCC, Eastern Cooperative Oncology Group ≤2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for ≥78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% α = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. RESULTS: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in ≥10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. CONCLUSION: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control.

Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib.

ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC.Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. CONCLUSIONS: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials.

Kaci Hickox: public health and the politics of fear.

Kaci Hickox was a nurse who worked with persons who were infected with Ebola in West Africa. When she returned to the United States, the governors of New Jersey and Maine intervened to confine her to inpatient quarantine despite the fact that she was asymptomatic and had no serological evidence of infection. She defied the quarantine which resulted in enormous public attention and discussion of quarantine and public fear. This article summarizes the case discussing the history of the case, the government actions, and the final legal rulings.

Off-target effects of c-MET inhibitors on thyroid cancer cells.

Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of eight thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of eight) were growth inhibited by two small molecule c-MET inhibitors (tivantinib and crizotinib) associated with apoptosis and G(2)-M cell-cycle arrest. However, crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. However, tivantinib was less potent than crizotinib at inhibiting c-MET phosphorylation, but was more potent than crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell-cycle arrest and apoptosis. Taken together, tivantinib and crizotinib have off-target(s) activity, contributing to their antitumor activity. In vivo study showed that crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (tivantinib and crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non-MET-targeting effects.

The Barnes case: taking difficult futility cases public.

Futility disputes are increasing and courts are slowly abandoning their historical reluctance to engage these contentious issues, particularly when confronted with inappropriate surrogate demands for aggressive treatment. Use of the judicial system to resolve futility disputes inevitably brings media attention and requires clinicians, hospitals, and families to debate these deep moral conflicts in the public eye. A recent case in Minnesota, In re Emergency Guardianship of Albert Barnes, explores this emerging trend and the complex responsibilities of clinicians and hospital administrators seeking to replace an unfaithful surrogate demanding aggressive therapy. Use of the courts requires the coordinated commitment of significant institutional resources, management of intense media scrutiny and individual and organizational courage to enter the unpredictable world of litigation. Given the dearth of legislative guidance on medical futility, individual clinicians and institutions will continue to bear the difficult responsibility for resolution of individual futility disputes. The Barnes case illustrates how one institution successfully used the judicial system to replace an unfaithful surrogate, cease the provision of inappropriate aggressive care, and stimulate a community dialogue about appropriate care at the end of life.

Arterial blood pressure and cardiovascular responses to yoga practice.

CONTEXT: Yoga is qualitatively different from any other mode of physical activity in that it consists of a unique combination of isometric muscular contractions, stretching exercises, relaxation techniques, and breathing exercises. In particular, yoga postures consist of systemic isometric contractions that are known to elicit marked increases in mean blood pressure that are not observed during dynamic exercise. Stretching can also induce increases in blood pressure and sympathetic nerve activity in the muscles. Currently, not much is known about changes in blood pressure and other cardiovascular responses to yoga practice. OBJECTIVE: The study intended to determine the acute effects of one session of hatha yoga practice on blood pressure and other cardiovascular responses. To gain insight into the long-term effects of yoga practice, both novice (n = 19) and advanced (n = 18) yoga practitioners were studied. DESIGN: The two groups were matched for age, gender, BMI, and blood pressure. SETTING: The setting was a research laboratory at a university. PARTICIPANTS: Thirty-six apparently healthy, nonobese, sedentary, or recreationally active individuals from the community participated in the study. Intervention The intervention comprised one session of yoga practice, in which participants followed a custom made instructional video providing a yoga routine that consisted of a series of 23 hatha-based yoga postures. OUTCOME MEASURES: Prior to arriving at the laboratory, each participant completed a research health questionnaire, a training-status questionnaire, and a yoga-experience questionnaire. Prior to the yoga practice, each participant's height, body fat percentage, trunk or lumbar flexibility, and arterial stiffness as assessed by carotid femoral pulse wave velocity (cfPWV) were measured. For each posture during the yoga practice, the study continuously measured systolic, mean, and diastolic blood pressures, heart rate, stroke volume, and cardiac output. RESULTS: Systolic, mean, and diastolic blood pressures increased significantly during the yoga practice. The magnitude of these increases in blood pressure was greatest with standing postures. Heart rate and cardiac output increased significantly during yoga practice, especially with standing postures. Overall, no differences existed in cardiovascular responses between the novice and advanced practitioners throughout the yoga testing session; cfPWV velocity was significantly and inversely associated with lumbar flexion but not with sit-and-reach test scores. CONCLUSIONS: The research team concluded that a variety of hatha yoga postures, especially standing postures, evoked significant increases in blood pressure. The elevation in blood pressure due to yoga practice was associated with increases in cardiac output and heart rate, which are responses similar to those observed in isometric exercise. The lack of obvious differences in blood pressure and other cardiovascular responses between novice and advanced yoga practitioners suggests that long-term yoga practice does not attenuate acute yoga responses.

Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study.

BACKGROUND: Tivantinib (ARQ 197), a selective oral inhibitor of MET, has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib. We aimed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma. METHODS: In this completed, multicentre, randomised, placebo-controlled, double-blind, phase 2 study, we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy. We randomly allocated patients 2:1 to receive tivantinib (360 mg twice-daily) or placebo until disease progression. The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia. Randomisation was done centrally by an interactive voice-response system, stratified by Eastern Cooperative Oncology Group performance status and vascular invasion. The primary endpoint was time to progression, according to independent radiological review in the intention-to-treat population. We assessed tumour samples for MET expression with immunohistochemistry (high expression was regarded as ≥2+ in ≥50% of tumour cells). This study is registered with ClinicalTrials.gov, number NCT00988741. FINDINGS: 71 patients were randomly assigned to receive tivantinib (38 at 360 mg twice-daily and 33 at 240 mg twice-daily); 36 patients were randomly assigned to receive placebo. At the time of analysis, 46 (65%) patients in the tivantinib group and 26 (72%) of those in the placebo group had progressive disease. Time to progression was longer for patients treated with tivantinib (1·6 months [95% CI 1·4-2·8]) than placebo (1·4 months [1·4-1·5]; hazard ratio [HR] 0·64, 90% CI 0·43-0·94; p=0·04). For patients with MET-high tumours, median time to progression was longer with tivantinib than for those on placebo (2·7 months [95% CI 1·4-8·5] for 22 MET-high patients on tivantinib vs 1·4 months [1·4-1·6] for 15 MET-high patients on placebo; HR 0·43, 95% CI 0·19-0·97; p=0·03). The most common grade 3 or worse adverse events in the tivantinib group were neutropenia (ten patients [14%] vs none in the placebo group) and anaemia (eight [11%] vs none in the placebo group). Eight patients (21%) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two (6%) patients in the 240 mg group. Four deaths related to tivantinib occurred from severe neutropenia. 24 (34%) patients in the tivantinib group and 14 (39%) patients in the placebo group had serious adverse events. INTERPRETATION: Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis, particularly for patients with MET-high tumours. Confirmation in a phase 3 trial is needed, with a starting dose of tivantinib 240 mg twice-daily. FUNDING: ArQule, Daiichi Sankyo (Daiichi Sankyo Group).