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Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George’s Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62–128]; P

Background The comparative efficacy of inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist (ICS/LAMA/LABA) triple therapy administered via single or multiple inhalers in patients with chronic obstructive pulmonary disease (COPD) has not been evaluated comprehensively. We conducted two replicate trials comparing single- with multiple-inhaler ICS/LAMA/LABA combination in COPD. Methods 207608 and 207609 were Phase IV, 12-week, randomized, double-blind, triple-dummy non-inferiority trials comparing once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg via Ellipta inhaler, with twice-daily budesonide/formoterol (BUD/FOR) 400/12 μg via metered-dose inhaler plus once-daily tiotropium (TIO) 18 μg via HandiHaler. Patients had symptomatic COPD and forced expiratory volume in 1 s (FEV1) 1 1 at Week 12. Secondary endpoints included CFB in trough FEV1 at Day 84 and 85. Other endpoints included serial FEV1 and health status outcomes at Week 12. Safety was evaluated descriptively. Results The modified per-protocol population included 720 and 711 patients in studies 207608 and 207609 (intent-to-treat population: 728 and 732). FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0–24-h FEV1 at Week 12 (Study 207608 treatment difference [95% confidence interval]: 15 mL [− 13, 43]; Study 207609: 11 mL [− 20, 41]). FF/UMEC/VI improved trough FEV1 CFB versus BUD/FOR+TIO at Day 84 and 85 (Day 85 treatment difference: Study 207608: 38 mL [10, 66]; Study 207609: 51 mL [21, 82]) and FEV1 at 12 and 24 h post-morning dose at Week 12 in both studies. No treatment differences were seen in health status outcomes. Safety profiles were similar between treatments; pneumonia occurred in 7 ( Conclusions FF/UMEC/VI was non-inferior to BUD/FOR+TIO for wmCFB in 0–24-h FEV1 at Week 12 in patients with COPD. Greater improvements in trough and serial FEV1 measurements at Week 12 with FF/UMEC/VI versus BUD/FOR+TIO, together with similar health status improvements and safety outcomes including the incidence of pneumonia, suggest that once-daily single-inhaler FF/UMEC/VI triple therapy is a viable option for patients looking to simplify their treatment regimen. Trial registration GSK (207608/207609; NCT03478683/NCT03478696).

BACKGROUND: Acutely ill and frail older adults have complex social and health care needs. It is important to understand how this complexity affects acute outcomes for admission to hospital. We validated a frailty index using routine admission laboratory tests with outcomes after patients were admitted to hospital. METHODS: In a prospective cohort of older adults admitted to a large tertiary hospital in the United Kingdom, we created a frailty index from routine admission laboratory investigations (FI-Laboratory) linked to data comprising hospital outcomes. We evaluated the association between the FI-Laboratory and total days spent in hospital, discharge to a higher level of care, readmission and mortality. RESULTS: Of 2552 admissions among 1750 older adults, we were able to generate FI-Laboratory values for 2254 admissions (88.3% of the cohort). More than half of admitted patients were women (55.3%) and the mean age was 84.6 (SD 14.0) years. We found that the FI-Laboratory correlated weakly with the Clinical Frailty Scale (CFS; r2 = 0.09). An increase in the CFS and the equivalent of 3 additional abnormal laboratory test results in the FI-Laboratory, respectively, were associated with an increased proportion of inpatient days (rate ratios [RRs] 1.43, 95% confidence interval [CI] 1.35–1.52; and 1.47, 95% CI 1.41–1.54), discharge to a higher level of care (odd ratios [ORs] 1.39, 95% CI 1.27–1.52; and 1.30, 95% CI 1.16–1.47) and increased readmission rate (hazard ratios [HRs] 1.26, 95% CI 1.17–1.37; and 1.18, 95% CI 1.11–1.26). Increases in the CFS and FI-Laboratory were associated with increased mortality HRs of 1.39 (95% CI 1.28–1.51) and 1.45 (95% CI 1.37–1.54), respectively. INTERPRETATION: We determined that FI-Laboratory, distinct from baseline frailty, could be used to predict risk of many adverse outcomes. The score is therefore a useful way to quantify the degree of acute illness in frail older adults.

Introduction This retrospective database study explored treatment patterns and potential off-label prescribing among patients newly prescribed fluticasone furoate/vilanterol (FF/VI) in a UK primary care setting. Methods In Europe, FF/VI is approved in two strengths: 100/25 µg for adults with chronic obstructive pulmonary disease (COPD) and 100/25 µg or 200/25 µg for treatment of asthma in patients aged 12 or older. Using electronic health records from the Clinical Practice Research Datalink, new users of FF/VI or other inhaled corticosteroid/long-acting beta-agonist fixed-dose combination products were identified and classified into one of three groups: COPD diagnosis, asthma diagnosis, and other diagnosis (not COPD or asthma). Results During 2014–2015, 4373 patients initiated FF/VI: 3380 on FF/VI 100/25 (65% in the COPD diagnosis group) and 993 on FF/VI 200/25 (51% in the asthma diagnosis group). During up to 12 months of follow-up, the median number (interquartile range) of prescriptions of the index strength issued per patient was 7 (2–8) for FF/VI 100/25 and 5 (2–8) for FF/VI 200/25; most new users did not change from the index strength prescribed (93.0% COPD; 89.7% asthma, of all patients initiating treatment with FF/VI). Potential off-label FF/VI prescribing in children

Background: SLS COPD was the first open-label randomised controlled trial demonstrating a reduction in moderate/severe COPD exacerbations with once-daily inhaled fluticasone furoate/vilanterol (FF/VI) in everyday clinical practice. Here we report FF/VI effectiveness and safety in predefined patient subgroups. Methods: Patients with COPD, exacerbation history, and receiving maintenance inhaler therapy, were randomised to initiate FF/VI 100/25 μg or continue usual care (UC) with 12 months’ follow-up. Annual rates of moderate/severe exacerbations (primary outcome), selected secondary outcomes, and incidence of pneumonia serious adverse events of special interest (SAESI) were compared between randomisation groups across various patient subgroups/baseline treatment strata. SAESI rates by actual treatment were also assessed. Results: Lower exacerbation rates were observed for FF/VI versus UC across all subgroups/strata, including ICS + LABA therapy subset (8.0% [0.1, 15.4]), except in patients without baseline airflow limitation (−0.5% [–29.8, 22.1]). Larger reductions compared to the overall analysis were observed for patients on ICS-containing regimens (excluding LAMA) before the study (15.6% [3.4, 26.3]), and with baseline CAT score

Evidence to support clinical decision making must be based on safety data that have been captured, analysed and interpreted in a robust and reliable way. Randomised real-world evidence (RRWE) studies provide the opportunity to evaluate the use of medicines in patients and settings representative of routine clinical practice. However, elements that underpin the design of RRWE studies can have a significant impact upon the analysis, interpretation and implications of safety data. In this narrative review, we use data from the Salford Lung Study; two prospective, 12-month, open-label, parallel-group, phase III randomised controlled trials conducted in primary care in the UK; to highlight the importance of capturing treatment modifications when attempting to evaluate safety events according to actual treatment exposure. We demonstrate that analysing safety data by actual treatment received (i.e. accounting for the treatment modifications that occur routinely in the primary care setting) provides additional insight beyond analysing according to randomised treatment strategy only. It is therefore proposed that understanding of safety data from RRWE trials can be optimised by analysing both by randomised group and by actual treatment received., Using results from the Salford Lung Study, this review demonstrates that the understanding of safety data from randomised real-world evidence studies can be optimised by analysing both actual treatment received and randomisation group https://bit.ly/3p7zPXU

Introduction In the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI or UMEC/VI dual therapy in patients with chronic obstructive pulmonary disease (COPD); however, pneumonia incidence was higher in FF-containing arms. As COPD is a growing problem in Asia, we compared the efficacy and safety of FF/UMEC/VI in Asia versus non-Asia regions. Methods IMPACT was a double-blind, 52-week trial in symptomatic COPD patients with ≥ 1 moderate/severe exacerbation in the prior year. This pre-specified analysis evaluated the annual rate of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George’s Respiratory Questionnaire total score, mortality, and safety (including pneumonia) in Asia versus non-Asia regions. Results The intent-to-treat population comprised 10,355 patients (Asia n = 1644 [16%]). Rate ratios (95% confidence intervals) for moderate/severe exacerbations with FF/UMEC/VI were 0.89 (0.76–1.05) versus FF/VI and 0.86 (0.71–1.04) versus UMEC/VI in Asia, and 0.84 (0.79–0.90) and 0.74 (0.68–0.80) in non-Asia. Efficacy of FF/UMEC/VI on other endpoints was similar in both regions. There was an increased incidence of investigator-reported pneumonia in patients in Asia (FF/UMEC/VI: 13%; FF/VI: 14%; UMEC/VI: 6%) compared with non-Asia (FF/UMEC/VI: 6%; FF/VI: 5%; UMEC/VI: 4%). The increased risk of pneumonia in patients in Asia was most marked in patients with lower body mass index, lower lung function, and taking inhaled corticosteroids. In post hoc analysis of adjudicated on-treatment all-cause mortality, probabilities of death were numerically lower in both regions with FF/UMEC/VI (Asia: 1.16%; non-Asia: 1.35%) and FF/VI (Asia: 1.77%; non-Asia: 1.21%) versus UMEC/VI (Asia: 1.91%; non-Asia: 2.23%). Conclusions FF/UMEC/VI provides similar benefits in COPD patients in Asia and non-Asia regions. Clinical benefits of treatment, including reduction in mortality risk, should be weighed against risk of pneumonia, taking account of all known risk factors. Trial Registration ClinicalTrials.gov identification, NCT02164513. Electronic supplementary material The online version of this article (10.1007/s41030-020-00136-3) contains supplementary material, which is available to authorized users.

Here we are presenting a novel method to study the sumoylation of proteins and their sub-cellular localization in mammalian cells and nematode oocytes. This method utilizes a recombinant modified SUMO-trapping protein fragment, kmUTAG, derived from the Ulp1 SUMO protease of the stress-tolerant budding yeast Kluyveromyces marxianus. We have adapted the properties of the kmUTAG for the purpose of studying sumoylation in a variety of model systems without the use of antibodies. For the study of SUMO, KmUTAG has several advantages when compared to antibody-based approaches. This stress-tolerant SUMO-trapping reagent is produced recombinantly, it recognizes native SUMO isoforms from many species, and unlike commercially available antibodies it shows reduced affinity for free, unconjugated SUMO. Representative results shown here include the localization of SUMO conjugates in mammalian tissue culture cells and nematode oocytes.

Background The Salford Lung Study (SLS) programme, encompassing two phase III pragmatic randomised controlled trials, was designed to generate evidence on the effectiveness of a once-daily treatment for asthma and chronic obstructive pulmonary disease in routine primary care using electronic health records. Objective The objective of this study was to describe and discuss the safety monitoring methodology and the challenges associated with ensuring patient safety in the SLS. Refinements to safety monitoring processes and infrastructure are also discussed. The study results are outside the remit of this paper. The results of the COPD study were published recently and a more in-depth exploration of the safety results will be the subject of future publications. Achievements The SLS used a linked database system to capture relevant data from primary care practices in Salford and South Manchester, two university hospitals and other national databases. Patient data were collated and analysed to create daily summaries that were used to alert a specialist safety team to potential safety events. Clinical research teams at participating general practitioner sites and pharmacies also captured safety events during routine consultations. Confidence in the safety monitoring processes over time allowed the methodology to be refined and streamlined without compromising patient safety or the timely collection of data. The information technology infrastructure also allowed additional details of safety information to be collected. Conclusion Integration of multiple data sources in the SLS may provide more comprehensive safety information than usually collected in standard randomised controlled trials. Application of the principles of safety monitoring methodology from the SLS could facilitate safety monitoring processes for future pragmatic randomised controlled trials and yield important complementary safety and effectiveness data. © 2016 The Authors Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice.In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 μg and vilanterol at a dose of 25 μg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis.The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups.In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study ClinicalTrials.gov number, NCT01551758 .).

An integrated analysis was performed using safety data from 18 randomized, parallel-group studies from the fluticasone furoate/vilanterol (FF/VI) GSK asthma clinical study program. Efficacy data from four pivotal studies were also analyzed. Data were integrated from 18 Phase IIb and Phase III clinical studies. Key treatment arms were FF/VI 200/25 µg, FF/VI 100/25 µg, FF 200 µg, FF 100 µg, VI [with inhaled corticosteroids (ICSs)] 25 µg, and placebo. Safety endpoints included adverse events (AEs), AEs of special interest, 24-h urinary cortisol, vital signs, electrocardiograms, and asthma composite endpoints (defined as asthma-related hospitalizations, intubations, or death). Key efficacy endpoints included lung function assessments and symptomatic measures. In total, 7229 patients were randomized to one of six key treatment groups. The most frequently experienced AEs across key treatment groups were headache, nasopharyngitis, and upper respiratory tract infection. A greater incidence of local steroid effects was reported with FF-containing treatment groups versus placebo. No statistically significant difference was observed in asthma composite endpoint (asthma-related hospitalizations, intubations, or death) analysis of all FF/VI doses versus all ICS doses. A statistically significant difference in trough forced expiratory volume in one second (FEV1), 0–24 h weighted mean FEV1, and rescue-free and symptom-free 24 h periods was reported between FF/VI and FF treatment groups in all studies except one (NCT01165138). There was no evidence of an increased safety risk associated with FF/VI versus FF, VI, or placebo. FF/VI improved lung function and symptomatic endpoints versus FF alone. These data support the positive benefit:risk ratio of FF/VI versus FF alone and of having two approved FF/VI strengths to ensure appropriate treatment for patients with different asthma severity. GSK.

This case series includes a single case of disseminated tuberculous disease due to Mycobacterium pinnipedii in a New Zealand fur seal (Arctocephalus forsteri), which was being cared for by a zoo in New Zealand. The remaining five pinnipeds in the colony underwent extensive mycobacterial disease surveillance over the following 4 yr, involving a total of 26 anesthetic procedures and numerous diagnostic tests that included comparative intradermal tuberculin skin tests, mycobacterial antibody serology, respiratory and gastric lavages, and computed tomography (CT) scans. An additional case of chronic sinusitis due to Mycobacterium marinum and Pseudomonas aeruginosa was identified in a California sea lion (Zalophus californianus). Results from CT and the respiratory lavages were the most helpful antemortem diagnostic tests for active mycobacterial disease in this case series. Of the remaining four animals, two were euthanatized and two remain alive, and none of them had evidence of active mycobacterial disease. Further mycobacterial disease surveillance in staff and animals was performed, and no other case was identified. There are no validated mycobacterial surveillance tests available for pinnipeds and so it remains unknown whether the two surviving pinnipeds are truly negative or whether they have latent mycobacterial infection that could develop into active mycobacterial disease in the future. For this reason, increased levels of biosecurity and quarantine remain permanently in place for the pinniped colony.

SUMO proteases of the SENP/Ulp family are master regulators of both sumoylation and desumoylation and regulate SUMO homeostasis in eukaryotic cells. SUMO conjugates rapidly increase in response to cellular stress, including nutrient starvation, hypoxia, osmotic stress, DNA damage, heat shock, and other proteotoxic stressors. Nevertheless, little is known about the regulation and targeting of SUMO proteases during stress. To this end we have undertaken a detailed comparison of the SUMO-binding activity of the budding yeast protein Ulp1 (ScUlp1) and its ortholog in the thermotolerant yeast Kluyveromyces marxianus, KmUlp1. We find that the catalytic UD domains of both ScUlp1 and KmUlp1 show a high degree of sequence conservation, complement a ulp1Δ mutant in vivo, and process a SUMO precursor in vitro. Next, to compare the SUMO-trapping features of both SUMO proteases we produced catalytically inactive recombinant fragments of the UD domains of ScUlp1 and KmUlp1, termed ScUTAG and KmUTAG respectively. Both ScUTAG and KmUTAG were able to efficiently bind a variety of purified SUMO isoforms and bound immobilized SUMO1 with nanomolar affinity. However, KmUTAG showed a greatly enhanced ability to bind SUMO and SUMO-modified proteins in the presence of oxidative, temperature and other stressors that induce protein misfolding. We also investigated whether a SUMO-interacting motif (SIM) in the UD domain of KmULP1 that is not conserved in ScUlp1 may contribute to the SUMO-binding properties of KmUTAG. In summary, our data reveal important details about how SUMO proteases target and bind their sumoylated substrates, especially under stress conditions. We also show that the robust pan-SUMO binding features of KmUTAG can be exploited to detect and study SUMO-modified proteins in cell culture systems.

SLS evaluated the effectiveness and safety of asthma medications in everyday clinical practice (Woodcock A et al. BMC Pulm Med 2015;15:160). Symptomatic patients (pts), on ICS (± LABA) initiated treatment with FF/VI (100/25, 200/25 µg od) or continued optimised UC for 52 wks. Electronic health records were used to collect data; clinic visits at start/end with phone calls wks 12, 24, 40. Primary endpoint for asthma control: % pts with asthma control test (ACT) ≥ 20 and/or increase of ≥ 3 at wk 24 for the primary effectiveness analysis (PEA) population (ITT pts with an ACT A total of 3,026 and 4,233 pts comprised the PEA and ITT, respectively. Mean age 49.8 yrs, 87% asthma ≥ 5 yrs, 36% on ICS, 64% ICS/LABA (ITT). At wk24, significantly greater % pts improved or achieved asthma control with initiating FF/VI (71%) vs. continuing on UC (56%); adjusted odds ratio 2.00 [95% CI 1.70,2.34]; p There were 42 pneumonia events: 24 in 23 pts (FF/VI) and 18 in 16 pts (UC) by randomised treatment arm; this corresponded to 21 in 20 pts (FF/VI) and 21 in 19 pts (UC) by treatment at time of pneumonia. There were 284 (13%) SAEs of similar types per arm. Initiating treatment with FF/VI demonstrated improved asthma control compared with continuing UC in everyday clinical practice.

Evidence for management of asthma comes from closely monitored efficacy trials done in highly selected patient groups. There is a need for randomised trials that are closer to usual clinical practice.We did an open-label, randomised, controlled, two-arm effectiveness trial at 74 general practice clinics in Salford and South Manchester, UK. Patients aged 18 years or older with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy were randomly assigned to initiate treatment with a once-daily inhaled combination of either 100 μg or 200 μg fluticasone furoate with 25 μg vilanterol or optimised usual care and followed up for 12 months. The primary endpoint was the percentage of patients who achieved an asthma control test (ACT) score of 20 or greater or an increase in ACT score from baseline of 3 or greater at 24 weeks (termed responders), in patients with a baseline ACT score less than 20 (the primary effectiveness analysis population). All effectiveness analyses were done according to the intention-to-treat principle. This study is registered with ClinicalTrials.gov, number NCT01706198.Between Nov 12, 2012, and Dec 16, 2016, 4725 patients were enrolled and 4233 randomly assigned to initiate treatment with fluticasone furoate and vilanterol (n=2114) or usual care (n=2119). 1207 patients (605 assigned to usual care, 602 to fluticasone furoate and vilanterol) had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. At week 24, the odds of being a responder were higher for patients who initiated treatment with fluticasone furoate and vilanterol than for those on usual care (977 [71%] of 1373 in the fluticasone furoate and vilanterol group vs 784 [56%] of 1399 in the usual care group; odds ratio [OR] 2·00 [95% CI 1·70-2·34], p0·0001). At week 24, the adjusted mean ACT score increased by 4·4 points from baseline in patients initiated with fluticasone furoate and vilanterol, compared with 2·8 points in the usual care group (difference 1·6 [95% CI 1·3-2·0], p0·0001). This result was consistent for the duration of the study. Pneumonia was uncommon, with no differences between groups; there was no difference in other serious adverse events between the groups.In patients with a general practitioner's diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined fluticasone furoate and vilanterol improved asthma control without increasing the risk of serious adverse events when compared with optimised usual care.GlaxoSmithKline.

To describe the gross and light microscopic characteristics of skin lesions observed on the ventral skin of captive Archey's frogs (Leiopelma archeyi) between 2000 and 2012, and to investigate their occurrence, possible aetiology and association with survival.Postmortem skin samples were obtained for histological evaluation from 37 frogs, with and without skin lesions, that died while in captivity at Auckland Zoo between 2000 and 2012. Four frogs with skin lesions were biopsied under general anaesthesia and samples used for both light and transmission electron microscopy. The records of 94 frogs held at the University of Otago and Auckland Zoo between 2000-2012 were reviewed, which included some frogs recently collected from the wild. Information about the occurrence of skin lesions, and mortality associated with skin lesions was collated.Grossly the skin lesions varied in appearance; most were circular, pale grey papules, which measured from0.5-1.5 mm in diameter with no umbilication. The overlying epidermis was not fragile and there was no associated inflammation. Contents often appeared clear or semi-transparent. Lesions were located predominantly on ventral surfaces including trunk, thighs, lower legs and forearms, and gular region, but not on digits. The number ranged from single to multiple, often confluent lesions covering the entire ventral surface of the frog. Histologically the lesions consisted of enlarged proliferating mucous glands that expanded the dermis and elevated the epidermis. They were semi-organised, solid or occasionally cavitated acinar structures with central lumina which sometimes contained mucus. Nuclei showed moderate anisokaryosis and mitotic figures were uncommon. Transmission electron microscopy did not show any infectious agents. Between 2000 and 2012, skin lesions were recorded in 35/94 (37%) frogs. The size and location of skin lesions varied over time, with some resolving and sometimes reappearing. Skin lesions were not associated with an increased risk of death.The skin lesions had the gross and microscopic characteristics of adenomatous hyperplasia of the dermal mucous glands.The aetiology of this adenomatous hyperplasia is unknown, but factors associated with the captive environment are the most likely cause. This is the first description of adenomatous hyperplasia of the cutaneous mucous glands in amphibians.

Pragmatic trials offer the opportunity to obtain real-life data on the relative effectiveness and safety of a treatment before or after market authorisation. This is the penultimate paper in a series of eight, describing the impact of design choices on the practical implementation of pragmatic trials. This paper focuses on the practical challenges of collecting and reporting safety data and of monitoring trial conduct while maintaining routine clinical care practice. Current ICH guidance recommends that, all serious adverse events (SAEs) and all drug-related events must be reported in an interventional trial. In line with current guidance, we propose a risk based approach to the collection of non-drug related non-serious AEs, and even serious events not related to treatment based on the risk profile of the medicine/class in the patient population of interest. Different options available to support the collection and reporting of safety data whilst minimizing study-related follow-up visits are discussed. A risk-based approach to monitoring trial conduct is also discussed, highlighting the difference in the balance of risks likely to occur in a pragmatic trial compared to traditional clinical trials, and the careful consideration that must be given to the mitigation and management of these risks in order to maintain routine care.

SLS is an open label RCT that aims to guide COPD treatment by generating effectiveness and safety data in a population intended to represent that seen in everyday clinical practice (Bakerly et al. Respir Res 2015;16:101). COPD patients >40 years with ≥1 exacerbation in the previous 3 years were randomized 1:1 to initiate treatment with FF/VI 100/25mcg OD or continue on usual maintenance therapy (UC) for 12 months. Safety monitoring was performed by telephone every 3 months (unless other contact); other data were collected in real-time using an integrated primary & secondary care electronic medical record to normalise the patient experience. Primary endpoint is annual rate of moderate/severe exacerbations. Based on 2799 ITT patients; baseline exacerbation rate was 2.01; pre-bronchodilator FEV 1 % predicted was 56%. 177 patients experienced an SAE of pneumonia 94 initiated on FF/VI; 83 on UC (Incidence ratio 1.1, 95% CI 0.9–1.5). The SAE profile was similar across the groups. In an everyday clinical practice setting treatment initiated with FF/VI significantly reduced the rate of exacerbations compared with UC. FF/VI was non-inferior to UC for incidence of pneumonia. GSK Funded (HZC115151; NCT01551758).

Purpose Cancer survivors have many medical and psychosocial needs that are unaddressed in the post-treatment period. Qualitative research was carried out to assess how a survivorship care plan created by oncologists could improve the quality of survivorship care. Participants and Methods Focus groups and interviews conducted with cancer survivors, nurses, primary care physicians, and oncologists provide insights into post-treatment follow-up practices and the acceptability and feasibility of providing survivors and referring physicians with a cancer survivorship care plan. Results Cancer survivors reported satisfaction with post-treatment medical care, but felt that their psychosocial needs were not met. Survivors expressed enthusiastic support for receipt of a follow-up care plan. Primary care physicians viewed themselves as playing an important role during the post-treatment period and indicated that a written care plan for follow-up would help them improve their survivorship practices. Nurses recognized the need to improve the care of cancer survivors and suggested that they could play an active role in creating and implementing cancer survivorship plans. Physicians providing oncology care acknowledged the value of survivorship care plans, but were not inclined to complete them because such plans would not reduce other reporting and communication requirements and would be burdensome to complete given their busy schedules. Conclusion Survivorship care planning is viewed favorably by consumers, nurses, and physicians, however there are several barriers to its adoption. Barriers may be overcome with: electronic medical records, changes in reporting requirements of insurers, advocacy on the part of patients, and incorporation of care planning in education and training programs.

In 2012, Duke University initiated a research project, funded by an unrestricted research grant from Millennium Laboratories, a drug testing company. The project focused on assessing the frequency and nature of questionable, unethical, and illegal business practices in the clinical drug testing industry and assessing the potential for establishing a business code of ethics. Laboratory leaders, clinicians, industry attorneys, ethicists, and consultants participated in the survey, were interviewed, and attended two face-to-face meetings to discuss a way forward.The study demonstrated broad acknowledgment of variations in the legal and regulatory environment, resulting in inconsistent enforcement of industry practices. Study participants expressed agreement that overtly illegal practices sometimes exist, particularly when laboratory representatives and clinicians discuss reimbursement, extent of testing, and potential business incentives with medical practitioners. Most respondents reported directly observing probable violations involving marketing materials, contracts, or, in the case of some individuals, directly soliciting people with offers of clinical supplies and other “freebies.”While many study respondents were skeptical that voluntary standards alone would eliminate questionable business practices, most viewed ethics codes and credentialing as an important first step that could potentially mitigate uneven enforcement, while improving quality of care and facilitating preferred payment options for credentialed parties. Many were willing to participate in future discussions and industry-wide initiatives to improve the environment.

Transitional cell carcinomas (TCC) of the urinary bladder were diagnosed in four related fishing cats (Prionailurus viverrinus). The major clinical sign in each case was persistent hematuria unresponsive to medical therapy. Cystotomy and biopsy provided an antemortem diagnosis in three of the fishing cats before euthanasia because of progression of clinical signs. The diagnosis was made in the fourth cat after euthanasia because of renal failure. Hematuria improved temporarily in one of the cats diagnosed antemortem and treated with piroxicam and carboplatin. Attempts to isolate a herpesvirus in two of the cats failed. Histopathologic appearance of the TCC was similar to that described for other species. TCC metastasis to the lungs was noted at necropsy in one cat; metastatic disease was not noted in the other fishing cats on gross or histopathologic examination. TCC of the urinary bladder appears to be more prevalent in fishing cats than in other species of domestic or nondomestic felids.

This paper presents the concept of the town hall meeting and discusses how it can be used as a forum for those who have been touched by cancer. It can be a platform for people to express their views about cancer, not only in the community but also nationally. Empowerment is the hallmark of a town hall meeting. Those who are in leadership positions in health care and elected officials and community leaders are given the opportunity to hear the opinions of people who represent a broad-based constituency of individuals affected by cancer. The idea of holding a town hall meeting was first introduced in the cancer community by the National Coalition for Cancer Survivorship NCCS) as a means of identifying issues, exchanging information and considering creative solutions to problems. The first town hall meeting was held in 1994 in conjunction with the NCCS annual assembly. Since then, utilizing the guidelines set forth by the NCCS, 30 or more town hall meetings have been held across the United States. Cancer survivors have, by and large, been responsible for garnering the necessary support for conducting a town hall in their local area. Organizations such as the American Cancer Society, the Leukemia Society of America, hospitals, clinics, pharmaceutical and healthcare companies and also noncancer groups, such as the YMCA, churches, and radio/T.V. stations, join with the cancer survivors in organizing the meeting, planning related displays, and advertising the event. In 1998, seven town hall meetings were sponsored jointly by OnCare and NCCS in advance and support of the upcoming THE MARCH- Coming Together To Conquer Cancer, a national rally held in Washington, D.C. in September 1998. Attendees at the meetings included not only cancer survivors and their families, but also healthcare professionals, local and state legislators, community leaders and the media. Results of the 1998 town hall meetings are discussed and compared with the topics identified during the meetings held in 1994-1996. Town hall participants were outspoken about what is needed in America if cancer is truly to become the nation's healthcare priority. They are asking for equal access to quality care, increases in financial backing for research, and more support for cancer advocacy efforts. Benefits of holding town hall meetings are identified.

The effect of endogenous interleukin-12 (IL-12) on the influenza virus immune response in BALB/c mice was evaluated. Following primary influenza virus infection, IL-12 mRNA and protein are detected in the lung, with live virus being required for cytokine induction. Endogenous IL-12 contributes to early NK cell-dependent gamma interferon (IFN-γ) production (days 3 and 5) but not late T-cell-dependent IFN-γ secretion (day 7). IL-12 contributes to the inhibition of early virus replication but is not required for virus clearance. IL-12 also modestly contributes to the activation of cytotoxic T lymphocytes. Thus, in this model of experimental influenza virus infection, endogenous IL-12 contributes primarily to the early development and activation of the innate immune response.

This report describes the investigations into the cause and treatment of metabolic bone disease (MBD) in captive native New Zealand frogs (Leiopelma spp.) and the role of fluoride in the disease. MBD was diagnosed in Leiopelma archeyi and Leiopelma hochstetteri in 2008 at three institutions: Auckland Zoo, Hamilton Zoo, and the University of Otago. Most of these frogs had originally been held at the University of Canterbury for several years (2000-2004) but some were collected directly from the wild. Radiographs on archived and live frogs showed that MBD had been present at Canterbury, but at a lower rate (3%) than in the current institutions (38-67%). Microcomputed tomography showed that the femoral diaphyses of the captive frogs at Auckland Zoo had greater bone volume, bone surface, cross-sectional thickness, and mean total cross-sectional bone perimeter, which is consistent with osteofluorosis. On histology of the same femurs, there was hyperplasia, periosteal growth, and thickening of trabeculae, which are also consistent with skeletal fluorosis. An increase in fluoride levels in the water supply preceded the rise in the incidence of the above pathology, further supporting the diagnosis of osteofluorosis. Analysis of long-standing husbandry practices showed that ultraviolet B (UVB) exposure and the dietary calcium:phosphorus ratio were deficient when compared with wild conditions-likely causing chronic underlying MBD. To prevent multifactorial MBD in captive Leiopelma, the authors recommend increasing dietary calcium by incorporating into the captive diet inherently calcium-rich invertebrates; increasing exposure to natural or artificial (UVB) light; and using defluoridated water. Addressing these three factors at Auckland Zoo reduced morbidity, bone fractures, and mortality rates.

The role of the adult oncologists in the area of pediatric cancer treatment previously has been unmeasured. A questionnaire bearing regarding the practice of 447 adult oncologists was administered in June 1991. The membership list of the Association of Community Cancer Centers was used to identify contact oncologists. One hundred thirty-one questionnaires (29.3%) were returned for analysis. The data reveal that 204 patients younger than 21 years of age were treated during the last year in 63 adult oncology practices. Most of these patients were more than 15 years of age. Only a minority (53) were treated in rural practices. In addition, only a minority (27%) of these patients are reported to be enrolled in clinical trials

Hearing preservation in acoustic neuroma surgery is possible in a limited number of cases. Although there have been many articles published about hearing preservation, there have been few studies of long-term hearing results, nor is it known if there is an increased rate of tumor recurrence when hearing preservation is attempted. Twenty-two patients who underwent a hearing preservation procedure via the retrosigmoid approach were selected from 80 consecutive patients with cerebellopontine angle tumors operated on from February 1984 to November 1987. Useful hearing was retained in 11 cases as reported in a previously published study. Seven patients continue to have useful hearing after 3 to 5 years; 3 have shown a gradual but slight decline. There has been no tumor recurrence in these patients, but 2 patients, operated on early in the series and who had lost hearing, had recurrent tumor.

Cancer care is evolving from a solo practitioner care delivery system based on tradition and anecdotal experience to a multidisciplinary, collaborative, science-driven paradigm. Evidence-based practice facilitates optimal care quality for patients with cancer and is effected for medical and nursing practitioners through clinical practice guideline implementation. Clinician education based on principles of adult learning is one method of implementing clinical practice guidelines in clinical practice. However, research demonstrates that conventional static methods of education do little to change behavior; instead, effective education incorporates interactive formats, provides feedback, and includes reminder and reinforcement strategies. The EDUCATE (Educating Clinicians to Achieve Treatment Guideline Effectiveness) Study offers one model for clinical practice guideline implementation using educational methods. A faculty of nurse educators, together with practice champions, carried out an intensive educational intervention comprised of multiple teaching/learning activities during a 12-month period in community oncology practices throughout the United States. In addition to an overview of clinical practice guidelines and educational methods that can be used for implementation of clinical practice guidelines, the obstacles faced and lessons learned through the EDUCATE Study are presented, along with recommendations for implementation in the practice setting.

Fungal disease in reptiles is common, and can often lead to fatal systemic disease. Of the many fungal species isolated from reptiles most are environmental saphrophytes. Predisposing factors to in...

Bacterial biofilms can initiate chronic infections that become difficult to eradicate. There is an unmet need for effective therapeutic strategies that control and inhibit the growth of these biofilms. Herein, light sensitive mesoporous silica nanoparticles (MSNs) with photothermal (PTT) and antimicrobial combined capabilities have been developed. These nanosystems have high therapeutic potential to affect the bacterial biofilm architecture and subsequently inhibit its growth. Nucleation of gold nanorods followed by the growth of a silica shell leads to a core@shell design (AuNR@MSN) with PTT properties. Incorporation of nitrosothiol groups (-SNO) with a heat liable linker, enables an enhanced nitric oxide release upon photothermal stimulation with near infrared radiation. Further loading of an antimicrobial molecule such as the levofloxacin (LEVO) antibiotic creates a unique nanoassembly with potential therapeutic efficacy against Staphylococcus aureus bacterial biofilms. A dispersion rate of the bacterial biofilm was evident when light stimuli is applied because impregnation of the nitrosothiol functionalized nanosystem with the antibiotic LEVO led to ca. 30% reduction but its illumination with near infrared (NIR) irradiation showed a biofilm reduction of ca. 90%, indicating that localized antimicrobial exposure and PTT improves the therapeutic efficacy. These findings envision the conception of near-infraredactivated nanoparticle carriers capable of combined therapy upon NIR irradiation, which enables photothermal therapy, together with the release of levofloxacin and nitric oxide to disrupt the integrity of bacterial biofilms and achieve a potent antimicrobial therapy., 23 pages, 5 figures