Implementing a tobacco-free workplace program at a substance use treatment center: a case study.

BACKGROUND: People with substance use disorders smoke cigarettes at much higher rates than the general population in the United States and are disproportionately affected by tobacco-related diseases. Many substance use treatment centers do not provide evidence-based tobacco cessation treatment or maintain comprehensive tobacco-free workplace policies. The goal of the current work is to identify barriers and facilitators to a successful and sustainable implementation of a tobacco-free workplace program, which includes a comprehensive tobacco-free policy and evidence-based cessation treatment services, in a substance use treatment center. METHODS: This study is based on an ethnographic approach and uses a qualitative case study design. Data were collected via interviews with staff (n = 6) and clients (n = 16) at the substance use treatment center and site visits (n = 8). Data were analyzed using thematic analysis guided by the extended Normalization Process Theory designed to inform the implementation of innovations in healthcare practice. RESULTS: Staff at the substance use treatment center supported the implementation of the program and shared a good understanding of the purpose of the intervention and its potential benefits. However, the study identified significant challenges faced by the center during implementation, including widespread tobacco use among clients, contributing to attitudes among staff that tobacco cessation was a low-priority problem due to a perceived lack of interest in quitting and inability to quit among their clients. We identified several factors that contributed to changing this attitude, including provision of tobacco training to staff, active leadership support, low number of staff members who smoked, and access to material resources, including nicotine replacement products. The implementation and active enforcement of a comprehensive tobacco-free workplace program contributed to a gradual change in attitudes and improved the provision of evidence-based tobacco cessation care at the substance use treatment center. CONCLUSIONS: Substance use treatment centers can integrate tobacco cessation practices in their daily operations, despite multiple challenges they face due to the complex behavioral health and socioeconomic needs of their clients. With proper support, substance use treatment centers can provide much needed tobacco cessation care to their clients who are disproportionately affected by tobacco-related health conditions and systemic health inequities.

Upper Respiratory Tract OC43 Infection Model for Investigating Airway Immune-Modifying Therapies.

Respiratory virus infections initiate and transmit from the upper respiratory tract (URT). Coronaviruses, including OC43, are a major cause of respiratory infection and disease. Failure to mount an effective antiviral immune response in the nasal mucosa increases the risk of severe disease and person-to-person transmission, highlighting the need for URT infection models to support the development of nasal treatments that improve coronavirus antiviral immunity. We aimed to determine if OC43 productively infected the mouse URT and would therefore be a suitable model to assess the efficacy and mechanism of action of nasal-targeting immune-modifying treatments. We administered OC43 via intranasal inoculation to wild-type Balb/c mice and assessed virus airway tropism (by comparing total respiratory tract vs. URT-only virus exposure) and characterized infection-induced immunity by quantifying specific antiviral cytokines and performing gene array assessment of immune genes. We then assessed the effect of immune-modulating therapies, including an immune-stimulating TLR2/6 agonist (INNA-X) and the immune-suppressing corticosteroid fluticasone propionate (FP). OC43 replicated in nasal respiratory epithelial cells, with peak viral RNA observed 2 days after infection. Prophylactic treatment with INNA-X accelerated expression of virus-induced IFN-λ and IFN-stimulated genes. In contrast, intranasal FP treatment increased nasal viral load by 2.4 fold and inhibited virus-induced IFN and IFN-stimulated gene expression. Prior INNA-X treatment reduced the immune-suppressive effect of FP. We demonstrate that the mouse nasal epithelium is permissive to OC43 infection and strengthen the evidence that TLR2 activation is a ß-coronavirus innate immune determinant and therapeutic target.

In vitro assessment of antibacterial and antiviral activity of three copper products after 200 rounds of simulated use.

Copper has well-documented antibacterial effects but few have evaluated it after prolonged use and against bacteria and viruses. Coupons from three copper formulations (solid, thermal coating, and decal applications) and carbon steel controls were subjected to 200 rounds simulated cleaning using a Wiperator™ and either an accelerated hydrogen peroxide, quaternary ammonium, or artificial sweat products. Antibacterial activity against S. aureus and P. aeruginosa was then evaluated using a modified Environmental Protection Agency protocol. Antiviral activity against coronavirus (229E) and norovirus (MNV-1) surrogates was assessed using the TCID50 method. Results were compared to untreated control coupons. One hour after inoculation, S. aureus exhibited a difference in log kill of 1.16 to 4.87 and P. aeruginosa a log kill difference of 3.39-5.23 (dependent upon copper product and disinfectant) compared to carbon steel. MNV-1 demonstrated an 87-99% reduction on each copper surfaces at 1 h and 99% reduction at 2 h compared to carbon steel. Similarly, coronavirus 229E exhibited a 97-99% reduction after 1 h and 90-99% after 2 h. Simulated use with artificial sweat did not hinder the antiviral nor the antibacterial activity of Cu surfaces. Self-sanitizing copper surfaces maintained antibacterial and antiviral activity after 200 rounds of simulated cleaning.

Prehospital continuous positive airway pressure (CPAP) for acute respiratory distress: a randomised controlled trial.

OBJECTIVE: To compare the efficacy of continuous positive airway pressure (CPAP) versus usual care for prehospital patients with severe respiratory distress. METHODS: We conducted a parallel group, individual patient, non-blinded randomised controlled trial in Western Australia between March 2016 and December 2018. Eligible patients were aged ≥40 years with acute severe respiratory distress of non-traumatic origin and unresponsive to initial treatments by emergency medical service (EMS) paramedics. Patients were randomised (1:1) to usual care or usual care plus CPAP. The primary outcomes were change in dyspnoea score and change in RR at ED arrival, and hospital length of stay. RESULTS: 708 patients were randomly assigned (opaque sealed envelope) to usual care (n=346) or CPAP (n=362). Compared with usual care, patients randomised to CPAP had a greater reduction in dyspnoea scores (usual care -1.0, IQR -3.0 to 0.0 vs CPAP -3.5, IQR -5.2 to -2.0), median difference -2.0 (95% CI -2.5 to -1.6); and RR (usual care -4.0, IQR -9.0 to 0.0 min-1 vs CPAP -8.0, IQR -14.0 to -4.0 min-1), median difference -4.0 (95% CI -5.0 to -4.0) min-1. There was no difference in hospital length of stay (usual care 4.2, IQR 2.1 to 7.8 days vs CPAP 4.8, IQR 2.5 to 7.9 days) for the n=624 cases admitted to hospital, median difference 0.36 (95% CI -0.17 to 0.90). CONCLUSIONS: The use of prehospital CPAP by EMS paramedics reduced dyspnoea and tachypnoea in patients with acute respiratory distress but did not impact hospital length of stay. TRIAL REGISTRATION NUMBER: ACTRN12615001180505.

Rhinovirus-induced CCL17 and CCL22 in Asthma Exacerbations and Differential Regulation by STAT6.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Organizational Characteristics and Readiness for Tobacco-Free Workplace Program Implementation Moderates Changes in Clinician's Delivery of Smoking Interventions within Behavioral Health Treatment Clinics.

BACKGROUND: Smoking is elevated amongst individuals with behavioral health disorders, but not commonly addressed. Taking Texas Tobacco Free is an evidence-based, tobacco-free workplace program that addresses this, in-part, by providing clinician training to treat tobacco use in local mental health authorities (LMHAs). This study examined organizational moderators of change in intervention delivery from pre- to post-program implementation. METHODS: LMHA leaders completed the Organizational Readiness for Implementing Change (ORIC) and provided organization demographics pre-implementation. Clinicians (N = 1237) were anonymously surveyed about their consistent use of the 5As (Asking about smoking; Advising clientele to quit; Assessing willingness to quit; Assisting them to quit; Arranging follow-up) pre- and post-program implementation. Adjusted generalized linear mixed models were used for analyses (responses nested within LMHAs), with interaction terms used to assess moderation effects. RESULTS: Clinician delivery of 5As increased pre- to post-implementation (p < .001). LMHAs with fewer employees (ref = ≤300) demonstrated greater increases in Asking, Assessing, and Assisting over time. LMHAs with fewer patients (ref = ≤10 000) evinced greater changes in Asking over time. Less initial ORIC Change Efficacy, Change Commitment, and Task Knowledge were each associated with greater pre- to post-implementation changes in Asking. Less initial Task Knowledge was associated with greater increases in Advising, Assessing, and Assisting. Finally, less initial Resource Availability was associated with greater increases in Assisting (all moderation term ps < .025). CONCLUSION: The smallest and least ready LMHAs showed the largest gains in tobacco cessation intervention delivery; thus, low initial readiness was not a barrier for program implementation, particularly when efficacy-building training and resources are provided. IMPLICATIONS: This study examined organizational moderators of increases in tobacco cessation treatment delivery over time following the implementation of a comprehensive tobacco-free workplace program within 20 of 39 LMHAs across Texas (hundreds of clinics; servicing >50% of the state) from 2013 to 2018. Overall, LMHAs with fewer employees and patients, and that demonstrated the least initial readiness for change, evinced greater gains in intervention delivery. Findings add to dissemination and implementation science by supporting that low initial readiness was not a barrier for this aspect of tobacco-free workplace program implementation when resources and clinician training sessions were provided.

Adrenaline and vasopressin for cardiac arrest.

BACKGROUND: Adrenaline and vasopressin are widely used to treat people with cardiac arrest, but there is uncertainty about the safety, effectiveness and the optimal dose. OBJECTIVES: To determine whether adrenaline or vasopressin, or both, administered during cardiac arrest, afford any survival benefit. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and DARE from their inception to 8 May 2018, and the International Liaison Committee on Resuscitation 2015 Advanced Life Support Consensus on Science and Treatment Recommendations. We also searched four trial registers on 5 September 2018 and checked the reference lists of the included studies and review papers to identify potential papers for review. SELECTION CRITERIA: Any randomised controlled trial comparing: standard-dose adrenaline versus placebo; standard-dose adrenaline versus high-dose adrenaline; and adrenaline versus vasopressin, in any setting, due to any cause of cardiac arrest, in adults and children. There were no language restrictions. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials for review, assessed risks of bias and extracted data, resolving disagreements through re-examination of the trial reports and by discussion. We used risk ratios (RRs) with 95% confidence intervals (CIs) to compare dichotomous outcomes for clinical events. There were no continuous outcomes reported. We examined groups of trials for heterogeneity. We report the quality of evidence for each outcome, using the GRADE approach. MAIN RESULTS: We included 26 studies (21,704 participants).Moderate-quality evidence found that adrenaline increased survival to hospital discharge compared to placebo (RR 1.44, 95% CI 1.11 to 1.86; 2 studies, 8538 participants; an increase from 23 to 32 per 1000, 95% CI 25 to 42). We are uncertain about survival to hospital discharge for high-dose compared to standard-dose adrenaline (RR 1.10, 95% CI 0.75 to 1.62; participants = 6274; studies = 10); an increase from 33 to 36 per 1000, 95% CI 24 to 53); standard-dose adrenaline versus vasopressin (RR 1.25, 95% CI 0.84 to 1.85; 6 studies; 2511 participants; an increase from 72 to 90 per 1000, 95% CI 60 to 133); and standard-dose adrenaline versus vasopressin plus adrenaline (RR 0.76, 95% CI 0.47 to 1.22; 3 studies; 3242 participants; a possible decrease from 24 to 18 per 1000, 95% CI 11 to 29), due to very low-quality evidence.Moderate-quality evidence found that adrenaline compared with placebo increased survival to hospital admission (RR 2.51, 95% CI 1.67 to 3.76; 2 studies, 8489 participants; an increase from 83 to 209 per 1000, 95% CI 139 to 313). We are uncertain about survival to hospital admission when comparing standard-dose with high-dose adrenaline, due to very low-quality evidence. Vasopressin may improve survival to hospital admission when compared with standard-dose adrenaline (RR 1.27, 95% CI 1.04 to 1.54; 3 studies, 1953 participants; low-quality evidence; an increase from 260 to 330 per 1000, 95% CI 270 to 400), and may make little or no difference when compared to standard-dose adrenaline plus vasopressin (RR 0.95, 95% CI 0.83 to 1.08; 3 studies; 3249 participants; low-quality evidence; a decrease from 218 to 207 per 1000 (95% CI 181 to 236).There was no evidence that adrenaline (any dose) or vasopressin improved neurological outcomes.The rate of return of spontaneous circulation (ROSC) was higher for standard-dose adrenaline versus placebo (RR 2.86, 95% CI 2.21 to 3.71; participants = 8663; studies = 3); moderate-quality evidence; an increase from 115 to 329 per 1000, 95% CI 254 to 427). We are uncertain about the effect on ROSC for the comparison of standard-dose versus high-dose adrenaline and standard-does adrenaline compared to vasopressin, due to very low-quality evidence. Standard-dose adrenaline may make little or no difference to ROSC when compared to standard-dose adrenaline plus vasopressin (RR 0.97, 95% CI 0.87 to 1.08; 3 studies, 3249 participants; low-quality evidence; a possible decrease from 299 to 290 per 1000, 95% CI 260 to 323).The source of funding was not stated in 11 of the 26 studies. The study drugs were provided by the manufacturer in four of the 26 studies, but neither drug represents a profitable commercial option. The other 11 studies were funded by organisations such as research foundations and government funding bodies. AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that standard-dose adrenaline compared to placebo improves return of spontaneous circulation, survival to hospital admission and survival to hospital discharge, but low-quality evidence that it did not affect survival with a favourable neurological outcome. Very low -quality evidence found that high-dose adrenaline compared to standard-dose adrenaline improved return of spontaneous circulation and survival to admission. Vasopressin compared to standard dose adrenaline improved survival to admission but not return of spontaneous circulation, whilst the combination of adrenaline and vasopressin compared with adrenaline alone had no effect on these outcomes. Neither standard dose adrenaline, high-dose adrenaline,vasopressin nor a combination of adrenaline and vasopressin improved survival with a favourable neurological outcome. Many of these studies were conducted more than 20 years ago. Treatment has changed in recent years, so the findings from older studies may not reflect current practice.

Influenza A virus infection dysregulates the expression of microRNA-22 and its targets; CD147 and HDAC4, in epithelium of asthmatics.

BACKGROUND: Specific microRNAs (miRNAs) play essential roles in airway remodeling in asthma. Infection with influenza A virus (IAV) may also magnify pre-existing airway remodeling leading to asthma exacerbation. However, these events remain to be fully defined. We investigated the expression of miRNAs with diverse functions including proliferation (miR-20a), differentiation (miR-22) or innate/adaptive immune responses (miR-132) in primary bronchial epithelial cells (pBECs) of asthmatics following infection with the H1N1 strain of IAV. METHODS: pBECs from subjects (n = 5) with severe asthma and non-asthmatics were cultured as submerged monolayers or at the air-liquid-interface (ALI) conditions and incubated with IAV H1N1 (MOI 5) for up to 24 h. Isolated miRNAs were subjected to Taqman miRNAs assays. We confirmed miRNA targets using a specific mimic and antagomir. Taqman mRNAs assays and immunoblotting were used to assess expression of target genes and proteins, respectively. RESULTS: At baseline, these miRNAs were expressed at the same level in pBECs of asthmatics and non-asthmatics. After 24 h of infection, miR-22 expression increased significantly which was associated with the suppression of CD147 mRNA and HDAC4 mRNA and protein expression in pBECs from non-asthmatics, cultured in ALI. In contrast, miR-22 remained unchanged while CD147 expression increased and HDAC4 remained unaffected in cells from asthmatics. IAV H1N1 mediated increases in SP1 and c-Myc transcription factors may underpin the induction of CD147 in asthmatics. CONCLUSION: The different profile of miR-22 expression in differentiated epithelial cells from non-asthmatics may indicate a self-defense mechanism against aberrant epithelial responses through suppressing CD147 and HDAC4, which is compromised in epithelial cells of asthmatics.

Induction of Therapeutic Hypothermia During Out-of-Hospital Cardiac Arrest Using a Rapid Infusion of Cold Saline: The RINSE Trial (Rapid Infusion of Cold Normal Saline).

BACKGROUND: Patients successfully resuscitated by paramedics from out-of-hospital cardiac arrest often have severe neurologic injury. Laboratory and observational clinical reports have suggested that induction of therapeutic hypothermia during cardiopulmonary resuscitation (CPR) may improve neurologic outcomes. One technique for induction of mild therapeutic hypothermia during CPR is a rapid infusion of large-volume cold crystalloid fluid. METHODS: In this multicenter, randomized, controlled trial we assigned adults with out-of-hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to 2 L of cold saline or standard care. The primary outcome measure was survival at hospital discharge; secondary end points included return of a spontaneous circulation. The trial was closed early (at 48% recruitment target) due to changes in temperature management at major receiving hospitals. RESULTS: A total of 1198 patients were assigned to either therapeutic hypothermia during CPR (618 patients) or standard prehospital care (580 patients). Patients allocated to therapeutic hypothermia received a mean (SD) of 1193 (647) mL cold saline. For patients with an initial shockable cardiac rhythm, there was a decrease in the rate of return of a spontaneous circulation in patients who received cold saline compared with standard care (41.2% compared with 50.6%, P=0.03). Overall 10.2% of patients allocated to therapeutic hypothermia during CPR were alive at hospital discharge compared with 11.4% who received standard care (P=0.71). CONCLUSIONS: In adults with out-of-hospital cardiac arrest, induction of mild therapeutic hypothermia using a rapid infusion of large-volume, intravenous cold saline during CPR may decrease the rate of return of a spontaneous circulation in patients with an initial shockable rhythm and produced no trend toward improved outcomes at hospital discharge. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01173393.

Synergistic Enhancement of Electrocatalytic CO2 Reduction with Gold Nanoparticles Embedded in Functional Graphene Nanoribbon Composite Electrodes.

Regulating the complex environment accounting for the stability, selectivity, and activity of catalytic metal nanoparticle interfaces represents a challenge to heterogeneous catalyst design. Here we demonstrate the intrinsic performance enhancement of a composite material composed of gold nanoparticles (AuNPs) embedded in a bottom-up synthesized graphene nanoribbon (GNR) matrix for the electrocatalytic reduction of CO2. Electrochemical studies reveal that the structural and electronic properties of the GNR composite matrix increase the AuNP electrochemically active surface area (ECSA), lower the requisite CO2 reduction overpotential by hundreds of millivolts (catalytic onset > -0.2 V versus reversible hydrogen electrode (RHE)), increase the Faraday efficiency (>90%), markedly improve stability (catalytic performance sustained over >24 h), and increase the total catalytic output (>100-fold improvement over traditional amorphous carbon AuNP supports). The inherent structural and electronic tunability of bottom-up synthesized GNR-AuNP composites affords an unrivaled degree of control over the catalytic environment, providing a means for such profound effects as shifting the rate-determining step in the electrocatalytic reduction of CO2 to CO, and thereby altering the electrocatalytic mechanism at the nanoparticle surface.

Addressing Tobacco Use Among Consumers and Staff at Behavioral Health Treatment Facilities Through Comprehensive Workplace Programming.

Tobacco use is the leading cause of death and disability in the United States; cigarette smoking is the most common form of tobacco use. Smoking has become increasingly concentrated among individuals with behavioral health needs (e.g., persistent mental illness) and has led to increased morbidity and mortality in this group relative to the general population. Comprehensive tobacco-free workplace programs are effective in reducing tobacco use and cigarette smoke exposure among behavioral health consumers and the individuals who serve them. Taking Texas Tobacco-Free (TTTF) represents an academic-community partnership formed to address tobacco use among consumers and employees at behavioral health clinics across Texas via the dissemination of an evidence-based, multicomponent tobacco-free workplace program. Program components of TTTF include tobacco-free campus policy implementation and enforcement, staff education about tobacco use hazards, provider training to regularly screen for and address tobacco dependence via intervention, and community outreach. These components, the nature of the academic-community partnership, the process of behavioral health facility involvement and engagement, and the benefits and challenges of implementation from the perspectives of the project team and participating clinic leaders are described. This information can guide similar academic and community partnerships and inform the implementation of other statewide tobacco-free workplace programming.

The genetic and epigenetic landscapes of the epithelium in asthma.

Asthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier against inhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functional abnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structural and functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Both genetic and environmental risk factors play important roles in the development of asthma with an increasing number of genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulate airway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In this review we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate gene association studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNA methylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that are functionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutic targets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identified with different technologies. Some potential biomarkers are IRAKM, PCDH1, ORMDL3/GSDMB, IL-33, CDHR3 and CST1 in airway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field, particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33). Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a major portion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential.

Committed to work but vulnerable: self-perceptions and mental health in NEET 18-year olds from a contemporary British cohort.

BACKGROUND: Labour market disengagement among youths has lasting negative economic and social consequences, yet is poorly understood. We compared four types of work-related self-perceptions, as well as vulnerability to mental health and substance abuse problems, among youths not in education, employment or training (NEET) and among their peers. METHODS: Participants were from the Environmental Risk (E-Risk) longitudinal study, a nationally representative UK cohort of 2,232 twins born in 1994-1995. We measured commitment to work, job-search effort, professional/technical skills, 'soft' skills (e.g. teamwork, decision-making, communication), optimism about getting ahead, and mental health and substance use disorders at age 18. We also examined childhood mental health. RESULTS: At age 18, 11.6% of participants were NEET. NEET participants reported themselves as committed to work and searching for jobs with greater diligence than their non-NEET peers. However, they reported fewer 'soft' skills (B = -0.98, p < .001) and felt less optimistic about their likelihood of getting ahead in life (B = -2.41, p < .001). NEET youths also had higher rates of concurrent mental health and substance abuse problems, but these did not explain the relationship with work-related self-perceptions. Nearly 60% of NEET (vs. 35% of non-NEET) youths had already experienced ≥1 mental health problem in childhood/adolescence. Associations of NEET status with concurrent mental health problems were independent of pre-existing mental health vulnerability. CONCLUSIONS: Our findings indicate that while NEET is clearly an economic and mental health issue, it does not appear to be a motivation issue. Alongside skills, work-related self-perceptions and mental health problems may be targets for intervention and service provision among this high-risk population.

Discovery of imidazo[1,2-a]-pyridine inhibitors of pan-PI3 kinases that are efficacious in a mouse xenograft model.

Alterations in PI3K/AKT signaling are known to be implicated with tumorigenesis. The PI3 kinases family of lipid kinases has been an attractive therapeutic target for cancer treatment. Imidazopyridine compound 1, a potent, selective, and orally available pan-PI3K inhibitor, identified by scaffold morphing of a benzothiazole hit, was further optimized in order to achieve efficacy in a PTEN-deleted A2780 ovarian cancer mouse xenograft model. With a hypothesis that a planar conformation between the core and the 6-heteroaryl ring will allow for the accommodation of larger 5'-substituents in a hydrophobic area under P-loop, SAR efforts focused on 5'-alkoxy heteroaryl rings at the 6-position of imidazopyridine and imidazopyridazine cores that have the same dihedral angle of zero degrees. 6'-Alkoxy 5'-aminopyrazines in the imidazopyridine series were identified as the most potent compounds in the A2780 cell line. Compound 14 with 1,1,1-trifluoroisopropoxy group at 6'-position demonstrated excellent potency and selectivity, good oral exposure in rats and in vivo efficacy in A2780 tumor-bearing mouse. Also, we disclose the X-ray co-crystal structure of one enantiomer of compound 14 in PI3Kα, confirming that the trifluoromethyl group fits nicely in the hydrophobic hot spot under P-loop.

Is it Appropriate for Patients to be Discharged at the Scene by Paramedics?

BACKGROUND: Outcomes of patients who are discharged at the scene by paramedics are not fully understood. OBJECTIVE: We aimed to describe the risk of re-presentation and/or death in prehospital patients discharged at the scene. METHODS: We conducted a retrospective cohort study using linked ambulance, emergency department (ED), and death data. We compared outcomes in patients who were discharged at the scene by paramedics with those who were transported to ED by paramedics and then discharged from ED between January 1 and December 31, 2013 in metropolitan Perth, Western Australia. Occurrences of subsequent ambulance requests, ED attendance, hospital admission and death were compared between those discharged at the scene and those discharged from ED. RESULTS: There were 47,330 patients during the study period, of whom 19,732 and 27,598 patients were discharged at the scene and from ED, respectively. Compared to those discharged from ED, those discharged at the scene were more likely to subsequently: request an ambulance (6.1% vs. 1.8%, adjusted odds ratio [adj OR] 3.4; 95% confidence interval [CI] 3.0-3.9), attend ED (4.6% vs. 1.4%, adj OR 3.3; 95% CI 2.8-3.8), be admitted to hospital (3.3% vs. 0.8%, adj OR 4.2; 95% CI 3.4-5.1). Those discharged at the scene tended towards an increased likelihood of death (0.2% vs. 0.1%, adj OR 1.8; 95% CI 0.99-3.2) within 24 hours of discharge compared to those discharged from ED. CONCLUSION: Patients attended by paramedics who were discharged at the scene had more subsequent events than those who were transported to and discharged from ED. Further consideration needs to be given to who is suitable to be discharged at the scene by paramedics.

Ordering in Polymer Micelle-Directed Assemblies of Colloidal Nanocrystals.

Assembly of presynthesized nanocrystals by block copolymer micelles can be rationalized by the incorporation of nanocrystals into micellar coronas of constant width. As determined by quantitative analysis using small-angle X-ray scattering, high loading of small nanocrystals yields composites exhibiting order on two length scales, whereas intermediate loading of nanocrystals larger than the coronal width produces single nanocrystal networks. The resulting structures obey expectations of thermodynamically driven assembly on the nanocrystal length scale, whereas kinetically frozen packing principles dictate order on the polymer micelle length scale.

Nanocomposite Architecture for Rapid, Spectrally-Selective Electrochromic Modulation of Solar Transmittance.

Two active electrochromic materials, vacancy-doped tungsten oxide (WO(3-x)) nanocrystals and amorphous niobium oxide (NbOx) glass are arranged into a mesostructured architecture. In a strategy applicable across electrochemical applications, the critical dimensions and interfacial connections in the nanocomposite are designed to optimize pathways for electrochemical charging and discharging. The result is an unprecedented optical range for modulation of visible and near-infrared solar radiation with rapid switching kinetics that indicate the WO(3-x) nanocrystal framework effectively pumps charge out of the normally sluggish NbOx glass. The material is durable for at least 2000 electrochemical cycles.

Challenges during long-term follow-up of ICU patients with and without chronic disease.

INTRODUCTION: Reflecting on researchers' experiences during follow-up of patients enrolled in research may lead to improved understanding of the challenges faced in maintaining contact when patients leave hospital. AIMS: (1) Describe the challenges researchers face when following-up patients who survive ICU. (2) Identify issues that influenced our ability to follow-up patients. METHODS: This sub-study was part of a larger "case-control" study investigating the quality of life of ICU survivors with and without pre-existing chronic disease. Patients completed self-assessment QLQ and symptom assessment before hospital discharge and at six months, plus they were asked to keep a paper diary of healthcare services used. Patient contact was maintained by monthly telephone calls. Each telephone call was logged and summaries of conversations documented. Our experience of conducting the study was reviewed by the identification of common issues which arose from the follow-up of patients. RESULTS: Thirty patients with a history of chronic disease and 30 patients without underlying chronic disease were followed-up. A total of 582 telephone calls were made for 60 patients discharged from hospital of which 261 (45%) calls led to a telephone interview. Only 19 (30%) of diaries were completed and returned. We identified six challenges associated with issues that arose from the follow-up of patients. CONCLUSION: We underestimated the number of telephone calls required for follow-up after discharge. Diaries were unreliable sources of data suggesting strategies are needed to improve compliance. How patients respond to follow-up is not always predictable. Processes are needed to deal with unexpected information provided during telephone follow-up.

Paramedic Differentiation of Asthma and COPD in the Prehospital Setting Is Difficult.

INTRODUCTION: Separate clinical practice guidelines (CPG) for asthma and chronic obstructive pulmonary disease (COPD) often guide prehospital care. However, having distinct CPGs implies that paramedics can accurately differentiate these conditions. We compared the accuracy of paramedic identification of these two conditions against the emergency department (ED) discharge diagnosis. METHODS: A retrospective cohort of all patients transported to ED by ambulance in Perth, Western Australia between July 2012 and June 2013; and identified as "asthma" or "COPD" by paramedics. We linked ambulance data to emergency department discharge diagnosis. RESULTS: Of 1,067 patients identified by paramedics as having asthma, 41% had an ED discharge diagnosis of asthma, i.e., positive predictive value (PPV) = 41% (95% CI 38-44%). Of 1,048 patients recorded as COPD, 57% had an ED discharge diagnosis of COPD (PPV 57%; 95% CI 54-60%). Sensitivity for the paramedic identification of patients diagnosed with asthma or COPD in the ED was 66% for asthma (95% CI 63-70%) and 39% for COPD (95% CI 36-41%). Paramedics reported wheezing in 86% of asthma and 55% of COPD patients. CONCLUSION: Differentiating between asthma and COPD in the prehospital setting is difficult. A single CPG for respiratory distress would be more useful for the clinical management of these patients by paramedics.