Macromolecular organic compounds from the depths of Enceladus.

Saturn's moon Enceladus harbours a global water ocean 1 , which lies under an ice crust and above a rocky core 2 . Through warm cracks in the crust 3 a cryo-volcanic plume ejects ice grains and vapour into space4-7 that contain materials originating from the ocean8,9. Hydrothermal activity is suspected to occur deep inside the porous core10-12, powered by tidal dissipation 13 . So far, only simple organic compounds with molecular masses mostly below 50 atomic mass units have been observed in plume material6,14,15. Here we report observations of emitted ice grains containing concentrated and complex macromolecular organic material with molecular masses above 200 atomic mass units. The data constrain the macromolecular structure of organics detected in the ice grains and suggest the presence of a thin organic-rich film on top of the oceanic water table, where organic nucleation cores generated by the bursting of bubbles allow the probing of Enceladus' organic inventory in enhanced concentrations.

A novel sulfur mustard (HD) vapor inhalation exposure model of pulmonary toxicity for the efficacy evaluation of candidate medical countermeasures.

OBJECTIVE: To develop a novel inhalation exposure system capable of delivering a controlled inhaled HD dose through an endotracheal tube to anesthetized rats to investigate the lung pathophysiology and evaluate potential medical countermeasures. MATERIALS AND METHODS: Target HD vapor exposures were generated by a temperature-controlled vapor generator, while concentration was monitored near real-time by gas chromatography. Animal breathing parameters were monitored real-time by in-line EMKA/SciReq pulmonary analysis system. Individual exposures were halted when the target inhaled doses were achieved. Animals were observed daily for clinical observations and lethality with scheduled termination at 28 days post-exposure. Upon scheduled or unscheduled death, animals underwent a gross necropsy and lung and trachea were collected for histopathology. RESULTS: Controlled HD concentrations ranged from 60 to 320 mg/m3. Delivered inhaled doses range from 0.3 to 3.20 mg/kg with administered doses within 3% of the target. The 28-day inhaled LD50 is 0.80 mg/kg (95% CI = 0.42-1.18 mg/kg). Post exposure respiratory abnormalities were observed across all dose levels though the higher dose levels had earlier onset and higher frequency of occurrence. Histopathologic alterations were not qualitatively altered in accordance with dose but instead showed a relationship to an animals' time of death, with early deaths demonstrating acute damage and later deaths displaying signs of repair. DISCUSSION/CONCLUSION: This novel exposure system administers targeted HD inhaled doses to generate a small animal model that can be used to evaluate physiological toxicities of inhaled HD on the lungs and for evaluation of potential medical countermeasure treatments.

Outcomes of Peripheral Vascular Interventions via Retrograde Pedal Access for Chronic Limb-Threatening Ischemia in a Multicenter Registry.

Purpose: To describe the use and 1-year outcomes of retrograde pedal access during peripheral vascular interventions (PVI) for chronic limb-threatening ischemia (CLTI). Materials and Methods: From October 2016 to September 2017, 159 patients (mean age 71±10 years; 112 men) undergoing PVI via retrograde pedal access were enrolled in the multicenter Vascular Quality Initiative (VQI) registry. The pedal access approach included retrograde femoral (40%), antegrade femoral (26%), retrograde to antegrade femoral (22%), and pedal only (11%). A comparator group of 1972 patients (mean age 69±12 years; 1129 men) having a contralateral retrograde femoral access was established for propensity matching, which resulted in 156 patients per group. Procedure characteristics, technical success, and access site complications were compared. Major adverse limb events (MALE) and amputation-free survival (AFS) at 1 year were analyzed using the Kaplan-Meier method and Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CI). Results: Technical failure was similar for retrograde femoral and pedal access (7% vs 13%, p=0.07). Complications were rare and included access site hematoma (2 vs 5, p=0.32) and target artery thrombosis (0 vs 2) for the femoral vs pedal access groups, respectively. The rates of MALE at 1 year were significantly lower after retrograde femoral access (24%) compared with pedal access (38%; log-rank p=0.01; HR 1.95, 95% CI 1.15 to 3.30). AFS estimates at 1 year were similar: 86% for retrograde femoral and 83% for pedal access (log-rank p=0.37; HR 1.32, 95% CI 0.73 to 2.39), as were major amputation estimates: 10% for retrograde femoral access and 13% for pedal access group (log-rank p=0.21; HR 1.58, 95% CI 0.77 to 3.26). Conclusion: In this analysis of multicenter registry data, retrograde pedal access in patients with CLTI had similar technical success and early complications in comparison with traditional contralateral retrograde femoral access. The rates of MALE were higher after pedal access but AFS was similar, indicating a tradeoff between limb salvage and repeat interventions.

Patient-initiated appointment systems for adults with chronic conditions in secondary care.

BACKGROUND: Missed hospital outpatient appointments is a commonly reported problem in healthcare services around the world; for example, they cost the National Health Service (NHS) in the UK millions of pounds every year and can cause operation and scheduling difficulties worldwide. In 2002, the World Health Organization (WHO) published a report highlighting the need for a model of care that more readily meets the needs of people with chronic conditions. Patient-initiated appointment systems may be able to meet this need at the same time as improving the efficiency of hospital appointments. OBJECTIVES: To assess the effects of patient-initiated appointment systems compared with consultant-led appointment systems for people with chronic or recurrent conditions managed in secondary care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and six other databases. We contacted authors of identified studies and conducted backwards and forwards citation searching. We searched for current/ongoing research in two trial registers. Searches were run on 13 March 2019. SELECTION CRITERIA: We included randomised trials, published and unpublished in any language that compared the use of patient-initiated appointment systems to consultant-led appointment systems for adults with chronic or recurrent conditions managed in secondary care if they reported one or more of the following outcomes: physical measures of health status or disease activity (including harms), quality of life, service utilisation or cost, adverse effects, patient or clinician satisfaction, or failures of the 'system'. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all references at title/abstract stage and full-text stage using prespecified inclusion criteria. We resolved disagreements though discussion. Two review authors independently completed data extraction for all included studies. We discussed and resolved discrepancies with a third review author. Where needed, we contacted authors of included papers to provide more information. Two review authors independently assessed the risk of bias using the Cochrane Effective Practice and Organisation of Care 'Risk of bias' tool, resolving any discrepancies with a third review author. Two review authors independently assessed the certainty of the evidence using GRADE. MAIN RESULTS: The 17 included randomised trials (3854 participants; mean age 41 to 76 years; follow-up 12 to 72 months) covered six broad health conditions: cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis and inflammatory bowel disease. The certainty of the evidence using GRADE ratings was mainly low to very low. The results suggest that patient-initiated clinics may make little or no difference to anxiety (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.68 to 1.12; 5 studies, 1019 participants; low-certainty evidence) or depression (OR 0.79 95% CI 0.51 to 1.23; 6 studies, 1835 participants; low-certainty evidence) compared to the consultant-led appointment system. The results also suggest that patient-initiated clinics may make little or no difference to quality of life (standardised mean difference (SMD) 0.12, 95% CI 0.00 to 0.25; 7 studies, 1486 participants; low-certainty evidence) compared to the consultant-led appointment system. Results for service utilisation (contacts) suggest there may be little or no difference in service utilisation in terms of contacts between the patient-initiated and consultant-led appointment groups; however, the effect is not certain as the rate ratio ranged from 0.68 to 3.83 across the studies (median rate ratio 1.11, interquartile (IQR) 0.93 to 1.37; 15 studies, 3348 participants; low-certainty evidence). It is uncertain if service utilisation (costs) are reduced in the patient-initiated compared to the consultant-led appointment groups (8 studies, 2235 participants; very low-certainty evidence). The results suggest that adverse events such as relapses in some conditions (inflammatory bowel disease and cancer) may have little or no reduction in the patient-initiated appointment group in comparison with the consultant-led appointment group (MD -0.20, 95% CI -0.54 to 0.14; 3 studies, 888 participants; low-certainty evidence). The results are unclear about any differences the intervention may make to patient satisfaction (SMD 0.05, 95% CI -0.41 to 0.52; 2 studies, 375 participants) because the certainty of the evidence is low, as each study used different questions to collect their data at different time points and across different health conditions. Some areas of risk of bias across all the included studies was consistently high (i.e. for blinding of participants and personnel and blinding of outcome assessment, other areas were largely of low risk of bias or were affected by poor reporting making the assessment unclear). AUTHORS' CONCLUSIONS: Patient-initiated appointment systems may have little or no effect on patient anxiety, depression and quality of life compared to consultant-led appointment systems. Other aspects of disease status and experience also appear to show little or no difference between patient-initiated and consultant-led appointment systems. Patient-initiated appointment systems may have little or no effect on service utilisation in terms of service contact and there is uncertainty about costs compared to consultant-led appointment systems. Patient-initiated appointment systems may have little or no effect on adverse events such as relapse or patient satisfaction compared to consultant-led appointment systems.

Systematic Review of the Effects of Cognitive and Behavioural Interventions on Fall-Related Psychological Concerns in Older Adults.

This systematic review aims to evaluate the efficacy of cognitive and behavioural interventions for improving falls-related psychological concerns. A systematic search yielded 8 randomised controlled trials eligible for inclusion. All studies compared a cognitive and behavioural intervention to a control. Meta-analysis showed that cognitive and behavioural treatments had beneficial effects on fear of falling outcomes [lower score better] immediately after treatment [random effects standardised mean difference (SMD): -0.3 (95% CI: -0.50 to -0.10)] and at longer term follow up [random effects SMD: -0.29 (95% CI: -0.49 to -0.09)]. Cognitive and behavioural treatments also showed a positive effect on falls efficacy outcomes [higher score better] immediately after treatment [fixed effects SMD: 0.19 (95% CI: 0.04 to 0.34)] and over the longer term [fixed effects SMD: 0.13 (95% CI:-0.00 to 0.25)]. However the clinical significance of these effects on fear of falling and falls efficacy was unclear. Further work is required with best-practice comparators over a longer follow-up period.

The anti-proliferative and anti-inflammatory response of COPD airway smooth muscle cells to hydrogen sulfide.

BACKBROUND: COPD is a common, highly debilitating disease of the airways, primarily caused by smoking. Chronic inflammation and structural remodelling are key pathological features of this disease caused, in part, by the aberrant function of airway smooth muscle (ASM). We have previously demonstrated that hydrogen sulfide (H2S) can inhibit ASM cell proliferation and CXCL8 release, from cells isolated from non-smokers. METHODS: We examined the effect of H2S upon ASM cells from COPD patients. ASM cells were isolated from non-smokers, smokers and patients with COPD (n = 9). Proliferation and cytokine release (IL-6 and CXCL8) of ASM was induced by FCS, and measured by bromodeoxyuridine incorporation and ELISA, respectively. RESULTS: Exposure of ASM to H2S donors inhibited FCS-induced proliferation and cytokine release, but was less effective upon COPD ASM cells compared to the non-smokers and smokers. The mRNA and protein expression of the enzymes responsible for endogenous H2S production (cystathionine-ß-synthase [CBS] and 3-mercaptopyruvate sulphur transferase [MPST]) were inhibited by H2S donors. Finally, we report that exogenous H2S inhibited FCS-stimulated phosphorylation of ERK-1/2 and p38 mitogen activated protein kinases (MAPKs), in the non-smoker and smoker ASM cells, with little effect in COPD cells. CONCLUSIONS: H2S production provides a novel mechanism for the repression of ASM proliferation and cytokine release. The ability of COPD ASM cells to respond to H2S is attenuated in COPD ASM cells despite the presence of the enzymes responsible for H2S production.

An inhalational swine model for the characterization of physiological effects and toxicological profile associated with cyanide poisoning.

Cyanides are highly toxic compounds that have been used as weapons of terrorism throughout history. Cyanide (CN) is acutely toxic by all routes of administration; however, inhalation is the main exposure route. To adequately test effective countermeasures against inhalational CN threats, robust and well-characterized animal models are needed. This paper describes the initial development of a hydrogen cyanide (HCN) exposure swine model for documenting the physiological effects and toxicological profile during and after HCN inhalation exposure. Animals were implanted with telemetry transmitters for heart rate (HR), blood pressure, and electrocardiogram monitoring, and vascular access ports for serial blood collections. Nine female swine were exposed to HCN concentrations of 500 ± 6 ppm while breathing parameters were monitored real-time. Inhaled HCN doses ranged from 2.02 to 2.83 mg/kg. Clinical signs included vocalization, agitation, salivation, respiratory distress and apnea. After HCN exposure initiation, systemic arterial pressure fell dramatically with a concomitant increase in HR. Blood samples were collected to determine CN blood levels using LC-MS/MS and blood gas analysis. In summary, the developed HCN inhalation swine model permitted documentation of the physiological effects associated with CN poisoning. This model could be used to evaluate potential CN medical countermeasures in the event of a public health emergency stemming from inhalational CN threats.

Development of a hydrogen cyanide inhalation exposure system and determination of the inhaled median lethal dose in the swine model.

OBJECTIVE: Cyanide is a highly toxic chemical, and acute exposure depletes cells and tissue of oxygen, depressing the respiratory, cardiovascular and neurological systems and potentially leading to death. Cyanide has been used as a weapon since ancient Rome and continues to pose a potential threat today. A well-characterized animal model is necessary for the development of novel methods of rapid detection and treatment. This manuscript describes the development of an inhalation exposure system designed to evaluate the lethality of acute cyanide inhalation in the porcine model. MATERIALS AND METHODS: A custom designed hydrogen cyanide (HCN) inhalation exposure system provided stable cyanide concentrations to un-anesthetized swine while monitoring respiratory parameters. Real-time respiratory monitoring, cyanide concentration and body weight were used to calculate inhaled doses. RESULTS: The inhalation exposure system generated controlled HCN ranging from 260 to 986 ppm to achieve inhaled doses between 1.78 and 3.97 mg/kg. Based on survival outcomes, the median lethal dose was determined to be 2.21 mg/kg, and the median lethal exposure level was 5893 mg min/m3. DISCUSSION: The ability of the HCN inhalation exposure system to deliver target inhaled doses and the determination of the inhaled median lethal dose in swine support the use of the exposure system and animal model for the evaluation of medical countermeasures of acute inhaled HCN toxicity.

Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (PVT1) as a novel regulator of the asthmatic phenotype in human airway smooth muscle.

BACKGROUND: The mechanism underlying nonsevere and severe asthma remains unclear, although it is commonly associated with increased airway smooth muscle (ASM) mass. Long noncoding RNAs (lncRNAs) are known to be important in regulating healthy primary airway smooth muscle cells (ASMCs), whereas changed expression has been observed in CD8 T cells from patients with severe asthma. METHODS: Primary ASMCs were isolated from healthy subjects (n = 9) and patients classified as having nonsevere (n = 9) or severe (n = 9) asthma. ASMCs were exposed to dexamethasone and FCS. mRNA and lncRNA expression was measured by using a microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine relevant biological pathways. Finally, the lncRNA plasmacytoma variant translocation 1 (PVT1) was inhibited by transfection of primary ASMCs with small interfering RNAs, and the effect on ASMC phenotype was examined. RESULTS: The mRNA expression profile was significantly different between patient groups after exposure to dexamethasone and FCS, and these were associated with biological pathways that might be relevant to the pathogenesis of asthma, including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in lncRNA expression, yet the expression of only one lncRNA (PVT1) is decreased in patients with corticosteroid-sensitive nonsevere asthma and increased in patients with corticosteroid-insensitive severe asthma. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASMCs from patients with severe asthma. CONCLUSIONS: lncRNAs are associated with the aberrant phenotype observed in ASMCs from asthmatic patients. Targeting PVT1 might be effective in reducing airway remodeling in asthmatic patients.

Technology-assisted self-testing and management of oral anticoagulation therapy: a qualitative patient-focused study.

BACKGROUND: Oral anticoagulation therapy requires regular blood testing to ensure therapeutic levels are maintained and excessive bleeding/clotting is avoided. Technology-assisted self-testing and management is seen as one of the key areas in which quality of care can be improved whilst reducing costs. Nevertheless, levels of patient engagement in self-testing and management remain low. To date, little research emphasis has been placed on understanding the patients' perspectives for low engagement. The typical approach adopted by healthcare providers is to provide patient education programmes, with the expectation that individual patients will change their behaviour and adopt new self-care strategies. However, if levels of patient engagement are to be increased, healthcare providers must also develop a better understanding of how their clinical service provision is perceived by patients and make adaptations. OBJECTIVE: To explore patient views, needs and expectations of an anticoagulation service and the self-testing and management services provided. METHODS: Interviews were conducted with 17 patients who currently engage in international normalised ratio (INR) self-testing and management. Thematic coding and analysis were carried out on the interview transcripts. RESULTS: Four high-level themes emerged from interviews: (i) role of clinic, (ii) motivations for self-testing, (iii) managing INR and (iv) trust. The clinic was seen as adding value in terms of specifying testing frequency, dosage profiles and calibrating equipment. Prompt communication from clinic to patient was also valued, although more personalised/real-time communication would help avoid feelings of isolation. Patients felt more in control as self-tester/managers and often took decisions about treatment adjustments themselves. However, some also manipulated their own test results to avoid 'unnecessary' interventions. CONCLUSIONS AND RECOMMENDATIONS: More personalised/real-time communication, pragmatic and collaborative patient-clinician partnerships and recognition of expert patient knowledge and expertise are needed if increased levels of engagement with self-testing and management service provision is to be realised.

BET bromodomains regulate transforming growth factor-ß-induced proliferation and cytokine release in asthmatic airway smooth muscle.

Airway smooth muscle (ASM) mass is increased in asthma, and ASM cells from patients with asthma are hyperproliferative and release more IL-6 and CXCL8. The BET (bromo- and extra-terminal) family of proteins (Brd2, Brd3, and Brd4) govern the assembly of histone acetylation-dependent chromatin complexes. We have examined whether they modulate proliferation and cytokine expression in asthmatic ASM cells by studying the effect of BET bromodomain mimics JQ1/SGCBD01 and I-BET762. ASM cells from healthy individuals and nonsevere and severe asthmatics were pretreated with JQ1/SGCBD01 and I-BET762 prior to stimulation with FCS and TGF-ß. Proliferation was measured by BrdU incorporation. IL-6 and CXCL8 release was measured by ELISA, and mRNA expression was measured by quantitative RT-PCR. ChIP using a specific anti-Brd4 antibody and PCR primers directed against the transcriptional start site of IL-6 and CXCL8 gene promoters was performed. Neither JQ1/SGCBD01 nor I-BET762 had any effect on ASM cell viability. JQ1/SGCBD01 and I-BET762 inhibited FCS+TGF-ß-induced ASM cell proliferation and IL-6 and CXCL8 release in healthy individuals (≥ 30 nM) and in nonsevere and severe asthma patients (≥100 nM), with the latter requiring higher concentrations of these mimics. JQ1/SGCBD01 reduced Brd4 binding to IL8 and IL6 promoters induced by FCS+TGF-ß. Mimics of BET bromodomains inhibit aberrant ASM cell proliferation and inflammation with lesser efficiency in those from asthmatic patients. They may be effective in reducing airway remodeling in asthma.

Evaluating the effectiveness of patient education and empowerment to improve patient-provider interactions in antiretroviral therapy clinics in Namibia.

In order to increase patient active engagement during patient-provider interactions, we developed and implemented patient training sessions in four antiretroviral therapy (ART) clinics in Namibia using a "Patient Empowerment" training curriculum. We examined the impact of these trainings on patient-provider interactions after the intervention. We tested the effectiveness of the intervention using a randomized parallel group design, with half of the 589 enrolled patients randomly assigned to receive the training immediately and the remaining randomized to receive the training 6 months later. The effects of the training on patient engagement during medical consultations were measured at each clinic visit for at least 8 months of follow-up. Each consultation was audiotaped and then coded using the Roter Interaction Analysis System (RIAS). RIAS outcomes were compared between study groups at 6 months. Using intention-to-treat analysis, consultations in the intervention group had significantly higher RIAS scores in doctor facilitation and patient activation (adjusted difference in score 1.19, p = .004), doctor information gathering (adjusted difference in score 2.96, p = .000), patient question asking (adjusted difference in score .48, p = .012), and patient positive affect (adjusted difference in score 2.08, p = .002). Other measures were higher in the intervention group but did not reach statistical significance. We have evidence that increased engagement of patients in clinical consultation can be achieved via a targeted training program, although outcome data were not available on all patients. The patient training program was successfully integrated into ART clinics so that the trainings complemented other services being provided.

Investigating the feasibility and acceptability of health psychology-informed obesity training for medical students.

Health psychologists have succeeded in identifying theory-congruent behaviour change techniques (BCTs) to prevent and reduce lifestyle-related illnesses, such as cardiovascular disease, cancers and diabetes. Obesity management discussions between doctors and patients can be challenging and are often avoided. Despite a clear training need, it is unknown how best to tailor BCT research findings to inform obesity-management training for future healthcare professionals. The primary objective of this descriptive study was to gather information on the feasibility and acceptability of delivering and evaluating health psychology-informed obesity training to UK medical students. Medical students (n = 41) attended an obesity management session delivered by GP tutors. Sessions were audio-recorded to enable fidelity checks. Acceptability of training was explored qualitatively. Tutors consistently delivered training according to the intervention protocol; and students and tutors found the training highly acceptable. This psychology-informed training can be delivered successfully by GP tutors and further research is warranted to explore its efficacy.

A reusable device for electrochemical applications of hydrogel supported black lipid membranes.

Black lipid membranes (BLMs) are significant in studies of membrane transport, incorporated proteins/ion transporters, and hence in construction of biosensor devices. Although BLMs provide an accepted mimic of cellular membranes, they are inherently fragile. Techniques are developed to stabilize them, such as hydrogel supports. In this paper, we present a reusable device for studies on hydrogel supported (hs) BLMs. These are formed across an ethylene tetrafluoroethylene (ETFE) aperture array supported by the hydrogel, which is during in situ polymerization covalently "sandwiched" between the ETFE substrate and a gold electrode microchip, thus allowing direct electrochemical studies with the integrated working electrodes. Using electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy and contact angle measurements, we demonstrate the optimized chemical modifications of the gold electrode microchips and plasma modification of the ETFE aperture arrays facilitating covalent "sandwiching" of the hydrogel. Both fluorescence microscopy and EIS were used to demonstrate the induced spontaneous thinning of a deposited lipid solution, leading to formation of stabilized hsBLMs on average in 10 min. The determined specific membrane capacitance and resistance were shown to vary in the range 0.31-0.49 µF/cm(2) and 45-65 kΩ cm(2), respectively, corresponding to partially solvent containing BLMs with an average life time of 60-80 min. The characterized hsBLM formation and devised equivalent circuit models lead to a schematic model to illustrate lipid molecule distribution in hydrogel-supported apertures. The functionality of stabilized hsBLMs and detection sensitivity of the platform were verified by monitoring the effect of the ion transporter valinomycin.

Characterization of a nose-only inhaled phosgene acute lung injury mouse model.

CONTEXT: Phosgene's primary mode of action is as a pulmonary irritant characterized by its early latent phase where life-threatening, non-cardiogenic pulmonary edema is typically observed 6-24 h post-exposure. OBJECTIVE: To develop an inhaled phosgene acute lung injury (ALI) model in C57BL/6 mice that can be used to screen potential medical countermeasures. METHODS: A Cannon style nose-only inhalation exposure tower was used to expose mice to phosgene (8 ppm) or air (sham). An inhalation lethality study was conducted to determine the 8 ppm median lethal exposure (LCt50) at 24 and 48 h post-exposure. The model was then developed at 1.2 times the 24 h LCt50. At predetermined serial sacrifice time points, survivors were euthanized, body and lung weights collected, and lung tissues processed for histopathology. Additionally, post-exposure clinical observations were used to assess quality of life. RESULTS AND DISCUSSION: The 24-hour LCt50 was 226 ppm*min (8 ppm for 28.2 min) and the 48-hour LCt50 was 215 ppm*min (8 ppm for 26.9 min). The phosgene exposed animals had a distinct progression of clinical signs, histopathological changes and increased lung/body weight ratios. Early indicators of a 1.2 times the 24-hour LCt50 phosgene exposure were significant changes in the lung-to-body weight ratios by 4 h post-exposure. The progression of clinical signs and histopathological changes were important endpoints for characterizing phosgene-induced ALI for future countermeasure studies. CONCLUSION: An 8 ppm phosgene exposure for 34 min (1.2 × LCt50) is the minimum challenge recommended for evaluating therapeutic interventions. The predicted higher mortality in the phosgene-only controls will help demonstrate efficacy of candidate treatments and increase the probability that a change in survival rate is statistically significant.

Right ventricular cardiomyopathies: a multidisciplinary approach to diagnosis.

The physiological importance of the right ventricle (RV) has been underestimated over the past years. Finally in the early 1950s through the 1970s, cardiac surgeons recognized the importance of RV function. Since then, the importance of RV function has been recognized in many acquired cardiac heart disease. RV can be mainly or together with left ventricle (LV) affected by inherited or acquired cardiomyopathy. In fact, RV morphological and functional remodeling occurs more common during cardiomyopathies than in ischemic cardiomyopathies and more closely parallels LV dysfunction. Moreover, there are some cardiomyopathy subtypes showing a predominant or exclusive involvement of the RV, and they are probably less known by cardiologists. The clinical approach to right ventricular cardiomyopathies is often challenging. Imaging is the first step to raise the suspicion and to guide the diagnostic process. In the differential diagnosis, cardiologists should consider athlete's heart, congenital heart diseases, multisystemic disorders, and inherited arrhythmias. However, a multiparametric and multidisciplinary approach, involving cardiologists, experts in imaging, geneticists, and pathologists with a specific expertise in these heart muscle disorders is required.

Implementing a patient-initiated review system in rheumatoid arthritis: a qualitative evaluation.

BACKGROUND: The management of Rheumatoid Arthritis (RA), a chronic relapsing condition primarily affecting joints usually entails regular hospital reviews with a specialist. These reviews can occur when the patient is well. This study forms part of a service evaluation of a system wide implementation of a patient initiated review appointment system which we have called Direct Access (DA). The aim was to explore the experiences of patients and staff of a DA system in order to understand the process of the implementation and to identify potential improvements. METHODS: Twenty-three patients with RA that had completed one year of follow-up on the DA system and seven healthcare professionals (HCPs) involved in the implementation of the DA review system took part in semi-structured interviews. Thematic analysis was used to analyse the interview data and field notes. RESULTS: Four themes emerged in the data: (1) building patient confidence and empowerment, (2) right place right time, (3) safety, (4) the everyday challenges of managing change. These show that in order for implementation to be successful the patient needs to have confidence in using a new system of requesting a medical review, which, in turn, needs to be offered quickly and in a setting convenient to both patient and clinician. Embedded in the change process need to be systems for ensuring regular disease monitoring and general issues surrounding team working, communication and ownership of the change process also need to be considered from the outset. CONCLUSION: The clinics offer increased patient autonomy and the opportunity for greater self-management of chronic disease. This fits with new models of care where the patient is considered to be 'the expert'.

Airway smooth muscle hyperproliferation is regulated by microRNA-221 in severe asthma.

Increased airway smooth muscle (ASM) mass is a feature of asthmatic airways, and could result from augmented proliferation. We determined whether proliferation and IL-6 release are abnormal in ASM cells (ASMCs) from patients with severe asthma, and whether these features could be mediated by microRNA-221 and microRNA-222, through modulation of the cyclin-dependent kinase inhibitors, p21(WAF1) and p27(kip1). ASMCs cultured from bronchial biopsies of healthy subjects and patients with nonsevere or severe asthma were studied. Proliferation was measured by the incorporation of bromodeoxyuridine and IL-6 by ELISA. FCS and transforming growth factor (TGF)-ß caused greater proliferation and IL-6 release in patients with severe compared with nonsevere asthma and normal subjects. FCS + TGF-ß inhibited p21(WAF1) and p27(kip1) expression, and increased microRNA-221 (miR-221) expression in ASMCs from individuals with severe asthma. miR-221, and not miR-222, mimics the increased proliferation and IL-6 release induced by FCS + TGF in healthy ASM, whereas in patients with severe asthma, the inhibition of miR-221, but not miR-222, inhibited proliferation and IL-6 release. miR-221 inhibition led to the increased expression of FCS + TGF-ß-induced p21(WAF1) and p27(kip1). Dexamethasone suppressed proliferation in healthy subjects, but not in subjects with asthma. IL-6 was less suppressible by dexamethasone in patients with nonsevere and severe asthma, compared with healthy subjects. miR-221 did not influence the effects of dexamethasone. ASM from patients with severe asthma shows greater proliferation and IL-6 release than in patients with nonsevere asthma, but both groups show corticosteroid insensitivity. miR-221 regulates p21(WAF1) and p27(kip1) expression levels. Furthermore, miR-221 regulates the hyperproliferation and IL-6 release of ASMCs from patients with severe asthma, but does not regulate corticosteroid insensitivity.