Postmortem tissue distribution of morphine and its metabolites in a series of heroin related deaths

The abuse of heroin (diamorphine) and heroin deaths are growing around the world. The interpretation of the toxicological results from suspected heroin deaths is notoriously difficult especially in cases where there may be limited samples. In order to help forensic practitioners with heroin interpretation we determined the concentration of morphine (M), morphine‐3‐glucuronide (M3G) and morphine‐6‐glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas) and vitreous humor in 44 heroin related deaths. The presence of 6‐monoacetylmorphine (6‐MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated LC‐MS/MS method with solid phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6‐MAM (100% of cases), and thus heroin use. The results of the M, M3G and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in 4 cases in muscle (3 cases in bone marrow) no morphine, morphine‐3‐glucuronide or morphine‐6‐glucuronide was detected, even though they were detected in other case samples. As always postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible

Efficacy of ginger (Zingiber officinale) in ameliorating chemotherapy-induced nausea and vomiting and chemotherapy-related outcomes: a systematic review update and meta-analysis

Background: Ginger has been proposed as an adjuvant treatment for chemotherapy-induced nausea and vomiting. Objective: The aim of this systematic review with meta-analyses is to evaluate, in adult cancer patients receiving chemotherapy, the effects of ginger supplementation dose and duration on the incidence, duration, and severity of chemotherapy-induced nausea and vomiting and outcomes related to chemotherapy-induced nausea and vomiting (eg, quality of life and fatigue), compared with placebo or standard antiemetic medication. Method: Five electronic databases were searched from database inception to April 2018. The quality of evidence was appraised with the Cochrane Risk of Bias tool and Grading of Recommendations, Assessment, Development, and Evaluation level. Data were pooled using Revman software. Results: Eighteen articles were analyzed. The likelihood of acute vomiting was reduced by 60% with ginger supplementation ≤1 g/day for duration >3 days, compared with control groups (odds ratio 0.4, 95% CI 0.17 to 0.81; P=0.01; n=3 studies; n=3 interventions; n=301 participants; I2=20%; Grading of Recommendations, Assessment, Development, and Evaluation level: Moderate). The likelihood of fatigue was reduced by 80% with ginger supplementation of any dose for duration 2=0%; Grading of Recommendations, Assessment, Development, and Evaluation level: Low). No statistically significant association was found between ginger and likelihood of overall or delayed vomiting, likelihood or severity of nausea, or other outcomes related to chemotherapy-induced nausea and vomiting. Conclusions: Ginger supplementation might benefit chemotherapy-induced vomiting as well as fatigue. Due to clinical heterogeneity, this systematic review update found no association between ginger and chemotherapy-induced nausea and other chemotherapy-induced nausea and vomiting-related outcomes. The results of this systematic review and meta-analysis provide a rationale for further research with stronger study designs, adequate sample sizes, standardized ginger products, and validated outcome measures to confirm efficacy of ginger supplementation and optimal dosing regimens.</p

The impact of therapeutics on mortality in hospitalised patients with COVID-19:systematic review and meta-analyses informing the European Respiratory Society living guideline

Hospitalised patients with coronavirus disease 2019 (COVID-19) have a high mortality rate. There are an increasing number of published randomised controlled trials for anti-inflammatory, anti-viral and other treatments. The European Respiratory Society Living Guidelines for the Management of Hospitalised Adults with COVID-19 were published recently, providing recommendations on appropriate pharmacotherapy.Patient, Intervention, Comparator and Outcomes questions for key interventions were identified by an international panel and systematic reviews were conducted to identify randomised controlled trials meeting the inclusion criteria. The importance of end-points were rated, and mortality was identified as the key "critical" outcome for all interventions. Random-effects meta-analysis was used to pool studies and provide effect estimates for the impact of treatments on mortality.Corticosteroids, hydroxychloroquine, azithromycin, remdesivir, anti-interleukin (IL)-6 monoclonal antibodies, colchicine, lopinavir/ritonavir and interferon-β have been reviewed.Our results found further evidence in support of the use of corticosteroids, particularly dexamethasone, and anti-IL-6 receptor monoclonal antibody therapy. These data support the need to identify additional therapies with beneficial effects on mortality

A systematic review of pharmacotherapeutic clinical trial end-points for bronchiectasis in adults

Bronchiectasis is an increasing clinical problem, but multiple recent clinical trials have failed to reach their primary end-point. Difficulties in achieving “positive” bronchiectasis trials is reflected in a lack of agreement from trialists and regulators on what are the optimal end-points. To evaluate the use of end-points in bronchiectasis trials, we conducted a systematic review of published bronchiectasis trials from 2008 to 2018 and extracted end-points used, definitions, methods of analysis and responsiveness. Our analysis shows that quality of life and exacerbation end-points are most frequently used. Trials using exacerbation end-points have been characterised by varying definitions, multiple methods of analysis and durations of follow-up. There are multiple quality of life tools for bronchiectasis (Quality of Life – Bronchiectasis questionnaire, St George's Respiratory Questionnaire, etc.). The majority of studies measure lung function (e.g. forced expiratory volume in 1 s), but this is shown to be nonresponsive to the majority of interventions. Microbiology end-points frequently show statistically significant differences in phase 2 antibiotic studies but their correlation with clinical end-points is unknown. This systematic review demonstrates a need for guidance to standardise definitions and design features to improve reproducibility and increase the likelihood of demonstrating statistically significant benefits with new therapies

Personalised anti-inflammatory therapy for bronchiectasis and cystic fibrosis:selecting patients for controlled trials of neutrophil elastase inhibition

Background Neutrophil elastase (NE) has been linked to lung neutrophil dysfunction in bronchiectasis and cystic fibrosis (CF), making NE inhibition a potential therapeutic target. NE inhibitor trials have given mixed result perhaps because not all patients have elevated airway NE activity. Methods We tested whether a single baseline sputum NE measurement or a combination of clinical parameters could enrich patient populations with elevated NE activity for “personalised medicine”. Intra- and interindividual variations of total and active NE levels in induced sputum from patients with CF or bronchiectasis were monitored over 14 days. Patients with established CF and bronchiectasis (n=5 per group) were recruited. NE was measured using three different methods: one total and two active NE assays. Subsequently, we analysed the association between clinical parameters and NE from a large bronchiectasis cohort study (n=381). Results All three assays showed a high degree of day-to-day variability (0–233% over 14 days). There were strong correlations found between all assays (p<0.0001). Despite high day-to-day variability, patients could be stratified into “high” or “low” groups based on moderate cut-off levels. In the bronchiectasis cohort study, factors most associated with high sputum NE levels were: Pseudomonas aeruginosa infection (β-estimate 11.5, 95% CI −6.0–29.0), sputum colour (β-estimate 10.4, 95% CI 4.3–16.6), Medical Research Council dyspnoea score (β-estimate 6.4, 95% CI 1.4–11.4) and exacerbation history (β-estimate 3.4, 95% CI 1.4–5.3). Collectively, P. aeruginosa infection, sputum colour and exacerbation frequency provided the greatest specificity for “high” NE (98.7%, 95% CI 7.0–99.6%). Conclusion These results show that patients with bronchiectasis and CF can be effectively divided into “high” or “low” groups, based on sputum NE assays or clinical inclusion criteria

The Atacama Cosmology Telescope: The LABOCA/ACT Survey of Clusters at All Redshifts

We present a multi-wavelength analysis of eleven Sunyaev Zel'dovich effect (SZE)-selected galaxy clusters (ten with new data) from the Atacama Cosmology Telescope (ACT) southern survey. We have obtained new imaging from the Large APEX Bolometer Camera (345GHz; LABOCA) on the Atacama Pathfinder EXperiment (APEX) telescope, the Australia Telescope Compact Array (2.1GHz; ATCA), and the Spectral and Photometric Imaging Receiver (250, 350, and $500\,\rm\mu m$; SPIRE) on the Herschel Space Observatory. Spatially-resolved 345GHz SZE increments with integrated S/N > 5 are found in six clusters. We compute 2.1GHz number counts as a function of cluster-centric radius and find significant enhancements in the counts of bright sources at projected radii $\theta < \theta_{2500}$. By extrapolating in frequency, we predict that the combined signals from 2.1GHz-selected radio sources and 345GHz-selected SMGs contaminate the 148GHz SZE decrement signal by ~5% and the 345GHz SZE increment by ~18%. After removing radio source and SMG emission from the SZE signals, we use ACT, LABOCA, and (in some cases) new Herschel SPIRE imaging to place constraints on the clusters' peculiar velocities. The sample's average peculiar velocity relative to the cosmic microwave background is $153\pm 383\,\rm km\,s^{-1}$.Comment: 19 pages, 11 figures, Accepted for Publication in The Astrophysical Journa

The Atacama Cosmology Telescope: the stellar content of galaxy clusters selected using the Sunyaev-Zel'dovich effect

We present a first measurement of the stellar mass component of galaxy clusters selected via the Sunyaev-Zel'dovich (SZ) effect, using 3.6 um and 4.5 um photometry from the Spitzer Space Telescope. Our sample consists of 14 clusters detected by the Atacama Cosmology Telescope (ACT), which span the redshift range 0.27 < z < 1.07 (median z = 0.50), and have dynamical mass measurements, accurate to about 30 per cent, with median M500 = 6.9 x 10^{14} MSun. We measure the 3.6 um and 4.5 um galaxy luminosity functions, finding the characteristic magnitude (m*) and faint-end slope (alpha) to be similar to those for IR-selected cluster samples. We perform the first measurements of the scaling of SZ-observables (Y500 and y0) with both brightest cluster galaxy (BCG) stellar mass and total cluster stellar mass (M500star). We find a significant correlation between BCG stellar mass and Y500 (E(z)^{-2/3} DA^2 Y500 ~ M*^{1.2 +/- 0.6}), although we are not able to obtain a strong constraint on the slope of the relation due to the small sample size. Additionally, we obtain E(z)^{-2/3} DA^2 Y500 ~ M500star^{1.0 +/- 0.6} for the scaling with total stellar mass. The mass fraction in stars spans the range 0.006-0.034, with the second ranked cluster in terms of dynamical mass (ACT-CL J0237-4939) having an unusually low total stellar mass and the lowest stellar mass fraction. For the five clusters with gas mass measurements available in the literature, we see no evidence for a shortfall of baryons relative to the cosmic mean value.Comment: Accepted for publication in MNRAS; 12 pages, 10 figure